|
1
|
Hamelin D, Scicluna M, Saadie I, Mostefai F, Grenier J, Baron C, Caron E, Hussin J. Predicting pathogen evolution and immune evasion in the age of artificial intelligence. Comput Struct Biotechnol J 2025; 27:1370-1382. [PMID: 40235636 PMCID: PMC11999473 DOI: 10.1016/j.csbj.2025.03.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/17/2025] Open
Abstract
The genomic diversification of viral pathogens during viral epidemics and pandemics represents a major adaptive route for infectious agents to circumvent therapeutic and public health initiatives. Historically, strategies to address viral evolution have relied on responding to emerging variants after their detection, leading to delays in effective public health responses. Because of this, a long-standing yet challenging objective has been to forecast viral evolution by predicting potentially harmful viral mutations prior to their emergence. The promises of artificial intelligence (AI) coupled with the exponential growth of viral data collection infrastructures spurred by the COVID-19 pandemic, have resulted in a research ecosystem highly conducive to this objective. Due to the COVID-19 pandemic accelerating the development of pandemic mitigation and preparedness strategies, many of the methods discussed here were designed in the context of SARS-CoV-2 evolution. However, most of these pipelines were intentionally designed to be adaptable across RNA viruses, with several strategies already applied to multiple viral species. In this review, we explore recent breakthroughs that have facilitated the forecasting of viral evolution in the context of an ongoing pandemic, with particular emphasis on deep learning architectures, including the promising potential of language models (LM). The approaches discussed here employ strategies that leverage genomic, epidemiologic, immunologic and biological information.
Collapse
Affiliation(s)
- D.J. Hamelin
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Mila - Quebec AI Institute, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - M. Scicluna
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Mila - Quebec AI Institute, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - I. Saadie
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - F. Mostefai
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Mila - Quebec AI Institute, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - J.C. Grenier
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
| | - C. Baron
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Mila - Quebec AI Institute, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - E. Caron
- CHU Sainte-Justine Research Center, Université de Montréal, Montréal, Quebec, Canada
- Yale Center for Immuno-Oncology, Yale Center for Systems and Engineering Immunology, Yale Center for Infection and Immunity, Yale School of Medicine, New Haven, CT, USA
| | - J.G. Hussin
- Montreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- Mila - Quebec AI Institute, Montréal, Quebec, Canada
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
- Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada
| |
Collapse
|
|
2
|
Nguyen HT, Chikata T, Zhang Y, Van Tran G, Gatanaga H, Oka S, Takiguchi M. Role of HLA-B*58:01-Restricted CD8+ T Cells in HIV-1 Subtype AE Infection. J Infect Dis 2025; 231:175-185. [PMID: 39250760 DOI: 10.1093/infdis/jiae448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 07/24/2024] [Accepted: 09/06/2024] [Indexed: 09/11/2024] Open
Abstract
HLA-B*58:01 and HLA-B*57 are protective alleles against human immunodeficiency virus type 1 (HIV-1) subtype B or C infection, whereas these HLA alleles have not been reported as protective in HIV-1 subtype AE infection. Although HLA-B*58:01-restricted and HLA-B*57-restricted HIV-1-specific CD8+ T cells have been thoroughly analyzed in subtype B or C infection, they have been only partially analyzed in subtype AE infection. We identified 6 HLA-B*58:01-restricted subtype AE epitopes in Vietnamese individuals infected with subtype AE. HLA-B*58:01-restricted T-cell responses to Gag epitopes, which may control disease progression in HLA-B*58:01+ and HLA-B*57+ individuals infected with subtype B or C, were not protective in subtype AE infection. These findings suggest that the loss of HLA-B*58:01-restricted T cells specific for some Gag epitopes and/or their reduced ability may account for the lack of protective effects conferred by HLA-B*58:01 in subtype AE infection.
Collapse
Affiliation(s)
- Hung The Nguyen
- Divisions of International Collaboration Research and Tokyo Joint Laboratory, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto/Tokyo, Japan
| | - Takayuki Chikata
- Divisions of International Collaboration Research and Tokyo Joint Laboratory, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto/Tokyo, Japan
| | - Yu Zhang
- Divisions of International Collaboration Research and Tokyo Joint Laboratory, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto/Tokyo, Japan
| | - Giang Van Tran
- Department of General Planning, National Hospital of Tropical Diseases, Hanoi, Vietnam
- Department of Infectious Diseases, Hanoi Medical University, Hanoi, Vietnam
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shinichi Oka
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masafumi Takiguchi
- Divisions of International Collaboration Research and Tokyo Joint Laboratory, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto/Tokyo, Japan
| |
Collapse
|
|
3
|
Neuner-Jehle N, Zeeb M, Thorball CW, Fellay J, Metzner KJ, Frischknecht P, Neumann K, Leeman C, Rauch A, Stöckle M, Huber M, Perreau M, Bernasconi E, Notter J, Hoffmann M, Leuzinger K, Günthard HF, Pasin C, Kouyos RD. Using viral diversity to identify HIV-1 variants under HLA-dependent selection in a systematic viral genome-wide screen. PLoS Pathog 2024; 20:e1012385. [PMID: 39116192 PMCID: PMC11335148 DOI: 10.1371/journal.ppat.1012385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 08/20/2024] [Accepted: 07/02/2024] [Indexed: 08/10/2024] Open
Abstract
The pathogenesis of HIV-1 infection is governed by a highly dynamic, time-dependent interaction between the host and the viral genome. In this study, we developed a novel systematic approach to assess the host-virus interaction, using average pairwise viral diversity as a proxy for time since infection, and applied this method to nearly whole viral genome sequences (n = 4,464), human leukocyte antigen (HLA) genotyping data (n = 1,044), and viral RNA load (VL) measurements during the untreated chronic phase (n = 829) of Swiss HIV Cohort Study participants. Our systematic genome-wide screen revealed for 98 HLA/viral-variant pairs a signature of immune-driven selection in the form of an HLA-dependent effect of infection time on the presence of HIV amino acid variants. Of these pairs, 12 were found to have an effect on VL. Furthermore, 28/58 pairs were validated by time-to-event analyses and 48/92 by computational HLA-epitope predictions. Our diversity-based approach allows a powerful and systematic investigation of the interaction between the virus and cellular immunity, revealing a notable subset of such interaction effects. From an evolutionary perspective, these observations underscore the complexity of HLA-mediated selection pressures on the virus that shape viral evolution and pathogenesis.
Collapse
Affiliation(s)
- Nadia Neuner-Jehle
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - Marius Zeeb
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - Christian W. Thorball
- Precision Medicine Unit, Biomedical Data Science Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Jacques Fellay
- Precision Medicine Unit, Biomedical Data Science Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
- School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Karin J. Metzner
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - Paul Frischknecht
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
| | - Kathrin Neumann
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
| | - Christine Leeman
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
| | - Andri Rauch
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marcel Stöckle
- Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Michael Huber
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - Matthieu Perreau
- Divisions of Immunology and Allergy, Lausanne University Hospital, Lausanne, Switzerland
| | - Enos Bernasconi
- Division of Infectious Diseases, Ente Ospedaliero Cantonale, Lugano, University of Geneva and University of Southern Switzerland, Lugano, Switzerland
| | - Julia Notter
- Division of Infectious Diseases, Infection Prevention and Travel Medicine, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
| | - Matthias Hoffmann
- Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital Olten, Olten, Switzerland
| | | | - Huldrych F. Günthard
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | - Chloé Pasin
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
- Collegium Helveticum, Zurich, Switzerland
| | - Roger D. Kouyos
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
| | | |
Collapse
|
|
4
|
Lewitus E, Li Y, Bai H, Pham P, Rolland M. HIV-1 Gag, Pol, and Env diversified with limited adaptation since the 1980s. mBio 2024; 15:e0174923. [PMID: 38329340 PMCID: PMC10936417 DOI: 10.1128/mbio.01749-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 01/02/2024] [Indexed: 02/09/2024] Open
Abstract
Knowledge of HIV-1 global sequence diversity is critical for developing an effective prophylactic against HIV-1 infection. We developed the Hervé platform to analyze and visualize trends in HIV-1 diversification. Using Hervé, we analyzed 4,830 Env, 4,407 Gag, and 3,002 Pol publicly available independent sequences corresponding to subtypes A1, A6, B, C, D, F1, and G and circulating recombinant forms (CRFs) 01_AE, 02_AG, and 07_BC; sequences were sampled between 1980 and 2020 from 82 countries. HIV-1 diversified with a median of 1.82 amino acid substitutions per year in Env, 0.297 in Gag, and 0.779 in Pol. Yet, Env subtype B diversification plateaued post-2000. Pairwise diversity within subtypes and CRFs increased by 41.82% (range = 24.85%-54.41%) in Env, 56.93% (15.38%-89.16%) in Gag, and 46.12% (11.70%-70.57%) in Pol. Consensus sequences based on sequences sampled in each decade remained relatively stable over time. Similarly, at antibody epitope sites, only 0-8 residues that were minority variants became consensus over time in any subtype/CRF and only one known drug resistance mutation site differed from the reference (subtype G). The apparent contradiction between the fast diversification of HIV-1 and its limited adaptation illustrates that HIV-1 evolution is not directional and its consensus is at the intersection of millions of within-host selective processes occurring in a star-like manner. While a consensus sequence is a better representation of HIV-1 diversity than any individual sequence, consensus sequences have progressively become more distant from the circulating sequences they represent. IMPORTANCE Global surveillance of HIV-1 sequences is critical for designing relevant prophylactic and therapeutic interventions to infection. We designed an open-source platform, Hervé, for analyzing and visualizing the diversification dynamics of HIV-1 protein sequences. We characterized the evolution of over 12,000 HIV-1 Env, Gag, and Pol protein sequences from 1980-2020 and found that, despite a steady increase in intra-subtype and circulating recombinant form diversity, the most frequent residue at each site, i.e., the consensus, has varied only moderately.
Collapse
Affiliation(s)
- Eric Lewitus
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
| | - Yifan Li
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
| | - Hongjun Bai
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
| | - Phuc Pham
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
| | - Morgane Rolland
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
- Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, Maryland, USA
| |
Collapse
|
|
5
|
Arman MS, Hasan MZ. A computational exploration of global and temporal dynamics of selection pressure on HIV-1 Vif polymorphism. Virus Res 2024; 341:199323. [PMID: 38237808 PMCID: PMC10831783 DOI: 10.1016/j.virusres.2024.199323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 01/12/2024] [Accepted: 01/15/2024] [Indexed: 01/21/2024]
Abstract
Virion infectivity factor (Vif), an accessory protein of HIV-1 (human immunodeficiency virus type 1), antagonizes host APOBEC3 protein (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3) or A3 via proteasomal degradation, facilitating viral replication. HLA (Human leukocyte antigens) alleles, host restriction factors, and error-prone reverse transcription contribute to the global polymorphic dynamics of HIV, impacting effective vaccine design. Our computational analysis of over 50,000 HIV-1 M vif sequences from the Los Alamos National Laboratory (LANL) database (1998-2021) revealed positive selection pressure on the vif gene (nonsynonymous to synonymous ratio, dn/ds=1.58) and an average entropy score of 0.372 in protein level. Interestingly, over the years (1998-2021), a decreasing trend of dn/ds (1.68 to 1.47) and an increasing trend of entropy (0.309 to 0.399) was observed. The predicted mutational frequency against Vif consensus sequence decreased over time (slope = -0.00024, p < 0.0001). Sequence conservation was observed in Vif functional motifs F1, F2, F3, G, BC box, and CBF β binding region, while variability was observed mainly in N- and C- terminal and Zinc finger region, which were dominantly under immune pressure by host HLA-I-restricted CD8+ T cell. Computational analysis of ∆∆Gstability through protein stability prediction tools suggested that missense mutation may affect Vif stability, especially in the Vif-A3 binding interface. Notably, mutations R17K and Y44F in F1 and G box were predicted to destabilize the Vif-A3 binding interface by altering bond formations with adjacent amino acids. Therefore, our analysis demonstrates Vif adaptation with host physiology by maintaining sequence conservation, especially in A3 interacting functional motifs, highlighting important therapeutic candidate regions of Vif against HIV-1 infections.
Collapse
Affiliation(s)
- Md Sakil Arman
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh
| | - Md Zafrul Hasan
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh.
| |
Collapse
|
|
6
|
Cannon L, Fehrman S, Pinzone M, Weissman S, O'Doherty U. Machine Learning Bolsters Evidence That D1, Nef, and Tat Influence HIV Reservoir Dynamics. Pathog Immun 2024; 8:37-58. [PMID: 38292079 PMCID: PMC10827039 DOI: 10.20411/pai.v8i2.621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/04/2023] [Indexed: 02/01/2024] Open
Abstract
Background The primary hurdle to curing HIV is due to the establishment of a reservoir early in infection. In an effort to find new treatment strategies, we and others have focused on understanding the selection pressures exerted on the reservoir by studying how proviral sequences change over time. Methods To gain insights into the dynamics of the HIV reservoir we analyzed longitudinal near full-length sequences from 7 people living with HIV between 1 and 20 years following the initiation of antiretroviral treatment. We used this data to employ Bayesian mixed effects models to characterize the decay of the reservoir using single-phase and multiphasic decay models based on near full-length sequencing. In addition, we developed a machine-learning approach utilizing logistic regression to identify elements within the HIV genome most associated with proviral decay and persistence. By systematically analyzing proviruses that are deleted for a specific element, we gain insights into their role in reservoir contraction and expansion. Results Our analyses indicate that biphasic decay models of intact reservoir dynamics were better than single-phase models with a stronger statistical fit. Based on the biphasic decay pattern of the intact reservoir, we estimated the half-lives of the first and second phases of decay to be 18.2 (17.3 to 19.2, 95%CI) and 433 (227 to 6400, 95%CI) months, respectively.In contrast, the dynamics of defective proviruses differed favoring neither model definitively, with an estimated half-life of 87.3 (78.1 to 98.8, 95% CI) months during the first phase of the biphasic model. Machine-learning analysis of HIV genomes at the nucleotide level revealed that the presence of the splice donor site D1 was the principal genomic element associated with contraction. This role of D1 was then validated in an in vitro system. Using the same approach, we additionally found supporting evidence that HIV nef may confer a protective advantage for latently infected T cells while tat was associated with clonal expansion. Conclusions The nature of intact reservoir decay suggests that the long-lived HIV reservoir contains at least 2 distinct compartments. The first compartment decays faster than the second compartment. Our machine-learning analysis of HIV proviral sequences reveals specific genomic elements are associated with contraction while others are associated with persistence and expansion. Together, these opposing forces shape the reservoir over time.
Collapse
Affiliation(s)
- LaMont Cannon
- Center for Biological Data Science, Virginia Commonwealth University, Richmond, Virginia
| | - Sophia Fehrman
- Center for Biological Data Science, Virginia Commonwealth University, Richmond, Virginia
| | - Marilia Pinzone
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sam Weissman
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Una O'Doherty
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
7
|
Tao K, Rhee SY, Tzou PL, Osman ZA, Pond SLK, Holmes SP, Shafer RW. HIV-1 Group M Capsid Amino Acid Variability: Implications for Sequence Quality Control of Genotypic Resistance Testing. Viruses 2023; 15:992. [PMID: 37112972 PMCID: PMC10143361 DOI: 10.3390/v15040992] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data. METHODS We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor naïve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence ≥ 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method. RESULTS 162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; p < 1 × 10-9) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; p = 0.0002). CONCLUSIONS Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-naïve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy.
Collapse
Affiliation(s)
- Kaiming Tao
- Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Soo-Yon Rhee
- Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Philip L. Tzou
- Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Zachary A. Osman
- Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | | | - Susan P. Holmes
- Department of Statistics, Stanford University, Stanford, CA 94305, USA
| | - Robert W. Shafer
- Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| |
Collapse
|
|
8
|
Impaired protective role of HLA-B*57:01/58:01 in HIV-1 CRF01_AE infection: a cohort study in Vietnam. Int J Infect Dis 2023; 128:20-31. [PMID: 36549550 DOI: 10.1016/j.ijid.2022.12.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/05/2022] [Accepted: 12/11/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Human Leukocyte Antigen HLA-B*57:01 and B*58:01 are considered anti-HIV-1 protective alleles. HLA-B*57:01/58:01-restricted HIV-1 Gag TW10 (TSTLQEQIGW, Gag residues 240-249) epitope-specific CD8+ T cell responses that frequently select for a Gag escape mutation, T242N, with viral fitness cost are crucial for HIV-1 control. Although this finding has been observed in cohorts where HIV-1 subtype B or C predominates, the protective impact of HLA-B*57:01/58:01 has not been reported in Southeast Asian countries where HIV-1 CRF01_AE is the major circulating strain. Here, the effect of HLA-B*57:01/58:01 on CRF01_AE infection was investigated. METHODS The correlation of HLA-B*57:01/58:01 with viral load and CD4 counts were analyzed in the CRF01_AE-infected Vietnamese cohort (N = 280). The impact of the T242N mutation on CRF01_AE replication capacity was assessed. RESULTS HLA-B*57:01/58:01-positive individuals mostly had HIV-1 with T242N (62/63) but showed neither a significant reduction in viral load nor increased CD4 counts relative to B*57:01/58:01-negative participants. In vitro and in vivo analyses revealed a significant reduction in viral fitness of CRF01_AE with T242N. In silico analysis indicated reduced presentation of epitopes in the context of CRF01_AE compared to subtype B or C in 10/16 HLA-B*57:01/58:01-restricted HIV-1 epitopes. CONCLUSION The protective impact of HLA-B*57:01/58:01 on CRF01_AE infection is impaired despite strong suppressive pressure by TW10-specific CD8+ T cells.
Collapse
|
|
9
|
A New HIV-1 K 28E 32-Reverse Transcriptase Variant Associated with the Rapid Expansion of CRF07_BC among Men Who Have Sex with Men. Microbiol Spectr 2022; 10:e0254522. [PMID: 36214682 PMCID: PMC9604004 DOI: 10.1128/spectrum.02545-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
HIV-1 CRF07_BC originated among injection drug users (IDUs) in China. After diffusing into men who have sex with men (MSM), CRF07_BC has shown a rapid expansion in this group; however, the mechanism remains unclear. Here, we identified a new K28E32 variant of CRF07_BC that was characterized by five specific mutations (E28K, K32E, E248V, K249Q, and T338S) in reverse transcriptase. This variant was mainly prevalent among MSM, and was overrepresented in transmission clusters, suggesting that it could have driven the rapid expansion of CRF07_BC in MSM, though founder effects cannot be ruled out. It was descended from an evolutionary intermediate accumulating four specific mutations and formed an independent phylogenetic node with an estimated origin time in 2003. The K28E32 variant was demonstrated to have significantly higher in vitro HIV-1 replication ability than the wild type. Mutations E28K and K32E play a critical role in the improvement of in vitro HIV-1 replication ability, reflected by improved reverse transcription activity. The results could allow public health officials to use this marker (especially E28K and K32E mutations in the reverse transcriptase (RT) coding region) to target prevention measures prioritizing MSM population and persons infected with this variant for test and treat initiatives. IMPORTANCE HIV-1 has very high mutation rate that is correlated with the survival and adaption of the virus. The variants with higher transmissibility may be more selective advantage than the strains with higher virulence. Several HIV-1 variants were previously demonstrated to be correlated with higher viral load and lower CD4 T cell count. Here, we first identified a new variant (the K28E32 variant) of HIV-1 CRF07_BC, described its origin and evolutionary dynamics, and demonstrated its higher in vitro HIV-1 replication ability than the wild type. We demonstrated that five RT mutations (especially E28K and K32E) significantly improve in vitro HIV-1 replication ability. The appearance of the new K28E32 variant was associated with the rapidly increasing prevalence of CRF07_BC among MSM.
Collapse
|
|
10
|
High Level of Pre-Treatment HIV-1 Drug Resistance and Its Association with HLA Class I-Mediated Restriction in the Pumwani Sex Worker Cohort. Viruses 2022; 14:v14020273. [PMID: 35215866 PMCID: PMC8879707 DOI: 10.3390/v14020273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 01/08/2023] Open
Abstract
Background: We analyzed the prevalence of pre-antiretroviral therapy (ART) drug resistance mutations (DRMs) in a Kenyan population. We also examined whether host HLA class I genes influence the development of pre-ART DRMs. Methods: The HIV-1 proviral DNAs were amplified from blood samples of 266 ART-naïve women from the Pumwani Sex Worker cohort of Nairobi, Kenya using a nested PCR method. The amplified HIV genomes were sequenced using next-generation sequencing technology. The prevalence of pre-ART DRMs was investigated. Correlation studies were performed between HLA class I alleles and HIV-1 DRMs. Results: Ninety-eight percent of participants had at least one DRM, while 38% had at least one WHO surveillance DRM. M184I was the most prevalent clinically important variant, seen in 37% of participants. The DRMs conferring resistance to one or more integrase strand transfer inhibitors were also found in up to 10% of participants. Eighteen potentially relevant (p < 0.05) positive correlations were found between HLA class 1 alleles and HIV drug-resistant variants. Conclusions: High levels of HIV drug resistance were found in all classes of antiretroviral drugs included in the current first-line ART regimens in Africa. The development of DRMs may be influenced by host HLA class I-restricted immunity.
Collapse
|
|
11
|
Collaboration of a Detrimental HLA-B*35:01 Allele with HLA-A*24:02 in Coevolution of HIV-1 with T Cells Leading to Poorer Clinical Outcomes. J Virol 2021; 95:e0125921. [PMID: 34523962 PMCID: PMC8577379 DOI: 10.1128/jvi.01259-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although mutant-specific T cells are elicited in some individuals infected with HIV-1 mutant viruses, the detailed characteristics of these T cells remain unknown. A recent study showed that the accumulation of strains expressing Nef135F, which were selected by HLA-A*24:02-restricted T cells, was associated with poor outcomes in individuals with the detrimental HLA-B*35:01 allele and that HLA-B*35:01-restricted NefYF9 (Nef135-143)-specific T cells failed to recognize target cells infected with Nef135F mutant viruses. Here, we investigated HLA-B*35:01-restricted T cells specific for the NefFF9 epitope incorporating the Nef135F mutation. Longitudinal T-cell receptor (TCR) clonotype analysis demonstrated that 3 types of HLA-B*35:01-restricted T cells (wild-type [WT] specific, mutant specific, and cross-reactive) with different T cell repertoires were elicited during the clinical course. HLA-B*35:01+ individuals possessing wild-type-specific T cells had a significantly lower plasma viral load (pVL) than those with mutant-specific and/or cross-reactive T cells, even though the latter T cells effectively recognized the mutant virus-infected cells. These results suggest that mutant-specific and cross-reactive T cells could only partially suppress HIV-1 replication in vivo. An ex vivo analysis of the T cells showed higher expression of PD-1 on cross-reactive T cells and lower expression of CD160/2B4 on the mutant-specific T cells than other T cells, implying that these inhibitory and stimulatory molecules are key to the reduced function of these T cells. In the present study, we demonstrate that mutant-specific and cross-reactive T cells do not contribute to the suppression of HIV-1 replication in HIV-1-infected individuals, even though they have the capacity to recognize mutant virus-infected cells. Thus, the collaboration of HLA-A*24:02 with the detrimental allele HLA-B*35:01 resulted in the coevolution of HIV-1 alongside virus-specific T cells, leading to poorer clinical outcomes. IMPORTANCE HIV-1 escape mutations are selected under pressure from HIV-1-specific CD8+ T cells. Accumulation of these mutations in circulating viruses impairs the control of HIV-1 by HIV-1-specific T cells. Although it is known that HIV-1-specific T cells recognizing mutant virus were elicited in some individuals infected with a mutant virus, the role of these T cells remains unclear. Accumulation of phenylalanine at HIV-1 Nef135 (Nef135F), which is selected by HLA-A*24:02-restricted T cells, led to poor clinical outcome in individuals carrying the detrimental HLA-B*35:01 allele. In the present study, we found that HLA-B*35:01-restricted mutant-specific and cross-reactive T cells were elicited in HLA-B*35:01+ individuals infected with the Nef135F mutant virus. These T cells could not effectively suppress HIV-1 replication in vivo even though they could recognize mutant virus-infected cells in vitro. Mutant-specific and cross-reactive T cells expressed lower levels of stimulatory molecules and higher levels of inhibitory molecules, respectively, suggesting a potential mechanism whereby these T cells fail to suppress HIV-1 replication in HIV-1-infected individuals.
Collapse
|
|
12
|
Effect of Difference in Consensus Sequence between HIV-1 Subtype A/E and Subtype B Viruses on Elicitation of Gag-Specific CD8 + T Cells and Accumulation of HLA-Associated Escape Mutations. J Virol 2021; 95:JVI.02061-20. [PMID: 33361435 PMCID: PMC8094948 DOI: 10.1128/jvi.02061-20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 12/09/2020] [Indexed: 01/14/2023] Open
Abstract
The Gag280 mutation is associated with HLA-C*01:02 but not with HLA-B*52:01 in subtype A/E-infected individuals, whereas this mutation is associated with HLA-B*52:01 but not with HLA-C*01:02 in subtype B infections. Although it is known that the Gag280 mutant is selected by HLA-B*52:01-restricted GagRI8 (Gag275-282)-specific T cells in subtype B infections, it remains unknown why this Gag280 mutation is associated with HLA-C*01:02 rather than HLA-B*52:01 in subtype A/E infections. The subtype B and A/E viruses have different consensus sequence, with Thr and Val at Gag280, respectively. To clarify the effect of this difference in Gag280 consensus sequence, we investigated the role of HLA-C*01:02-restricted GagYI9 (Gag277-285)-specific T cells in selection of Gag280 mutations in subtype A/E-infected Vietnamese and subtype B-infected Japanese individuals. GagYI9-4V-specific T cells, which were frequently elicited in Vietnamese individuals infected with the consensus-type A/E virus, failed to recognize GagV280T mutant A/E virus-infected cells. GagYI9-4T mutant epitope-specific T cells, which were weakly elicited in individuals infected with the mutant A/E virus, had weak or no ability to recognize the mutant virus. These results account for the mechanism for selection and accumulation of GagV280T mutants in the case of subtype A/E infections. In contrast, HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in Japanese individuals infected with the subtype B virus, explaining why HLA-C*01:02-restricted Gag280 mutations are not accumulated in the case of a subtype B infection. The present study demonstrated that a difference in the Gag280 consensus sequence influenced the elicitation of the GagYI9-specific T cells involved in the accumulation of HLA-C*01:02-associated Gag280 mutations.IMPORTANCE HIV-1 mutations escaped from HIV-specific CD8+ T cells are mostly detected as HLA-associated mutations. A diversity of HLA-associated mutations is somewhat distinct to each race and region, since HLA allele distribution differs among them. A difference in the consensus sequence among HIV-1 subtypes may also influence the diversity of HLA-associated mutations. HLA-C*01:02-associated GagV280T and HLA-B*52:01-associated GagT280A/S mutations were previously identified in HIV-1 subtype A/E-infected and subtype B-infected individuals, respectively, though these subtype viruses have a different consensus sequence at Gag280. We demonstrated that the GagV280T mutant virus was selected by HLA-C*01:02-restricted GagYI9-4V-specific T cells in subtype A/E-infected Vietnamese but that HLA-C*01:02-restricted GagYI9-4T-specific T cells were weakly elicited in subtype B-infected Japanese. Together with our recent study which demonstrated the mechanism for the accumulation of HLA-B*52:01-associated mutations, we clarified the mechanism for the accumulation of different Gag280 mutations and the effect of the difference in the consensus sequence on the accumulation of escape mutations.
Collapse
|
|
13
|
Akahoshi T, Gatanaga H, Kuse N, Chikata T, Koyanagi M, Ishizuka N, Brumme CJ, Murakoshi H, Brumme ZL, Oka S, Takiguchi M. T-cell responses to sequentially emerging viral escape mutants shape long-term HIV-1 population dynamics. PLoS Pathog 2020; 16:e1009177. [PMID: 33370400 PMCID: PMC7833229 DOI: 10.1371/journal.ppat.1009177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/25/2021] [Accepted: 11/18/2020] [Indexed: 11/18/2022] Open
Abstract
HIV-1 strains harboring immune escape mutations can persist in circulation, but the impact of selection by multiple HLA alleles on population HIV-1 dynamics remains unclear. In Japan, HIV-1 Reverse Transcriptase codon 135 (RT135) is under strong immune pressure by HLA-B*51:01-restricted and HLA-B*52:01-restricted T cells that target a key epitope in this region (TI8; spanning RT codons 128-135). Major population-level shifts have occurred at HIV-1 RT135 during the Japanese epidemic, which first affected hemophiliacs (via imported contaminated blood products) and subsequently non-hemophiliacs (via domestic transmission). Specifically, threonine accumulated at RT135 (RT135T) in hemophiliac and non-hemophiliac HLA-B*51:01+ individuals diagnosed before 1997, but since then RT135T has markedly declined while RT135L has increased among non-hemophiliac individuals. We demonstrated that RT135V selection by HLA-B*52:01-restricted TI8-specific T-cells led to the creation of a new HLA-C*12:02-restricted epitope TN9-8V. We further showed that TN9-8V-specific HLA-C*12:02-restricted T cells selected RT135L while TN9-8T-specific HLA-C*12:02-restricted T cells suppressed replication of the RT135T variant. Thus, population-level accumulation of the RT135L mutation over time in Japan can be explained by initial targeting of the TI8 epitope by HLA-B*52:01-restricted T-cells, followed by targeting of the resulting escape mutant by HLA-C*12:02-restricted T-cells. We further demonstrate that this phenomenon is particular to Japan, where the HLA-B*52:01-C*12:02 haplotype is common: RT135L did not accumulate over a 15-year longitudinal analysis of HIV sequences in British Columbia, Canada, where this haplotype is rare. Together, our observations reveal that T-cell responses to sequentially emerging viral escape mutants can shape long-term HIV-1 population dynamics in a host population-specific manner.
Collapse
Affiliation(s)
| | - Hiroyuki Gatanaga
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Nozomi Kuse
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
| | - Takayuki Chikata
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
| | - Madoka Koyanagi
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | | | - Chanson J. Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Hayato Murakoshi
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
| | - Zabrina L. Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
- Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
| | - Shinichi Oka
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masafumi Takiguchi
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
- Division of International Collaboration Research, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Tokyo, Japan
- * E-mail:
| |
Collapse
|
|
14
|
Impaired ability of Nef to counteract SERINC5 is associated with reduced plasma viremia in HIV-infected individuals. Sci Rep 2020; 10:19416. [PMID: 33173092 PMCID: PMC7656250 DOI: 10.1038/s41598-020-76375-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 10/28/2020] [Indexed: 01/23/2023] Open
Abstract
HIV-1 Nef plays an essential role in enhancing virion infectivity by antagonizing the host restriction molecule SERINC5. Because Nef is highly polymorphic due to the selective forces of host cellular immunity, we hypothesized that certain immune-escape polymorphisms may impair Nef’s ability to antagonize SERINC5 and thereby influence viral fitness in vivo. To test this hypothesis, we identified 58 Nef polymorphisms that were overrepresented in HIV-infected patients in Japan sharing the same HLA genotypes. The number of immune-associated Nef polymorphisms was inversely correlated with the plasma viral load. By breaking down the specific HLA allele-associated mutations, we found that a number of the HLA-B*51:01-associated Y120F and Q125H mutations were most significantly associated with a reduced plasma viral load. A series of biochemical experiments showed that the double mutations Y120F/Q125H, but not either single mutation, impaired Nef’s ability to antagonize SERINC5 and was associated with decreasing virion infectivity and viral replication in primary lymphocytes. In contrast, other Nef functions such as CD4, CCR5, CXCR4 and HLA class I downregulation and CD74 upregulation remained unchanged. Taken together, our results suggest that the differential ability of Nef to counteract SERINC5 by naturally occurring immune-associated mutations was associated with the plasma viral load in vivo.
Collapse
|
|
15
|
Warren JA, Zhou S, Xu Y, Moeser MJ, MacMillan DR, Council O, Kirchherr J, Sung JM, Roan NR, Adimora AA, Joseph S, Kuruc JD, Gay CL, Margolis DM, Archin N, Brumme ZL, Swanstrom R, Goonetilleke N. The HIV-1 latent reservoir is largely sensitive to circulating T cells. eLife 2020; 9:57246. [PMID: 33021198 PMCID: PMC7593086 DOI: 10.7554/elife.57246] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 09/24/2020] [Indexed: 01/01/2023] Open
Abstract
HIV-1-specific CD8+ T cells are an important component of HIV-1 curative strategies. Viral variants in the HIV-1 reservoir may limit the capacity of T cells to detect and clear virus-infected cells. We investigated the patterns of T cell escape variants in the replication-competent reservoir of 25 persons living with HIV-1 (PLWH) durably suppressed on antiretroviral therapy (ART). We identified all reactive T cell epitopes in the HIV-1 proteome for each participant and sequenced HIV-1 outgrowth viruses from resting CD4+ T cells. All non-synonymous mutations in reactive T cell epitopes were tested for their effect on the size of the T cell response, with a≥50% loss defined as an escape mutation. The majority (68%) of T cell epitopes harbored no detectable escape mutations. These findings suggest that circulating T cells in PLWH on ART could contribute to control of rebound and could be targeted for boosting in curative strategies.
Collapse
Affiliation(s)
- Joanna A Warren
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States
| | - Shuntai Zhou
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United States.,UNC Center For AIDS Research, University of North Carolina, Chapel Hill, United States
| | - Yinyan Xu
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States
| | - Matthew J Moeser
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United States.,UNC Center For AIDS Research, University of North Carolina, Chapel Hill, United States
| | | | - Olivia Council
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United States
| | - Jennifer Kirchherr
- Department of Medicine, University of North Carolina, Chapel Hill, United States
| | - Julia M Sung
- Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - Nadia R Roan
- Department of Urology, University of California San Francisco, San Francisco, United States.,Gladstone Institute of Virology and Immunology, San Francisco, United States
| | - Adaora A Adimora
- Department of Medicine, University of North Carolina, Chapel Hill, United States
| | - Sarah Joseph
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - JoAnn D Kuruc
- Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - Cynthia L Gay
- Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - David M Margolis
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.,UNC Center For AIDS Research, University of North Carolina, Chapel Hill, United States.,Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - Nancie Archin
- Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - Zabrina L Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.,Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
| | - Ronald Swanstrom
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.,Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, United States.,UNC Center For AIDS Research, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| | - Nilu Goonetilleke
- Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, United States.,Department of Medicine, University of North Carolina, Chapel Hill, United States.,UNC HIV Cure Center, University of North Carolina, Chapel Hill, United States
| |
Collapse
|
|
16
|
Abrahams MR, Joseph SB, Garrett N, Tyers L, Moeser M, Archin N, Council OD, Matten D, Zhou S, Doolabh D, Anthony C, Goonetilleke N, Karim SA, Margolis DM, Pond SK, Williamson C, Swanstrom R. The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation. Sci Transl Med 2020; 11:11/513/eaaw5589. [PMID: 31597754 DOI: 10.1126/scitranslmed.aaw5589] [Citation(s) in RCA: 135] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 08/29/2019] [Indexed: 12/12/2022]
Abstract
Although antiretroviral therapy (ART) is highly effective at suppressing HIV-1 replication, the virus persists as a latent reservoir in resting CD4+ T cells during therapy. This reservoir forms even when ART is initiated early after infection, but the dynamics of its formation are largely unknown. The viral reservoirs of individuals who initiate ART during chronic infection are generally larger and genetically more diverse than those of individuals who initiate therapy during acute infection, consistent with the hypothesis that the reservoir is formed continuously throughout untreated infection. To determine when viruses enter the latent reservoir, we compared sequences of replication-competent viruses from resting peripheral CD4+ T cells from nine HIV-positive women on therapy to viral sequences circulating in blood collected longitudinally before therapy. We found that, on average, 71% of the unique viruses induced from the post-therapy latent reservoir were most genetically similar to viruses replicating just before ART initiation. This proportion is far greater than would be expected if the reservoir formed continuously and was always long lived. We conclude that ART alters the host environment in a way that allows the formation or stabilization of most of the long-lived latent HIV-1 reservoir, which points to new strategies targeted at limiting the formation of the reservoir around the time of therapy initiation.
Collapse
Affiliation(s)
- Melissa-Rose Abrahams
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Sarah B Joseph
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Nigel Garrett
- Centre for the AIDS Programme of Research in South Africa, University of KwaZulu- Natal, Durban 4013, South Africa
| | - Lynn Tyers
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Matthew Moeser
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Nancie Archin
- UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Olivia D Council
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - David Matten
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Shuntai Zhou
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Deelan Doolabh
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Colin Anthony
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa
| | - Nilu Goonetilleke
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Salim Abdool Karim
- Centre for the AIDS Programme of Research in South Africa, University of KwaZulu- Natal, Durban 4013, South Africa.,Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA
| | - David M Margolis
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.,UNC HIV Cure Center and Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sergei Kosakovsky Pond
- Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Carolyn Williamson
- Division of Medical Virology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa. .,National Health Laboratory Services of South Africa, University of Cape Town, Cape Town 7925, South Africa
| | - Ronald Swanstrom
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. .,Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| |
Collapse
|
|
17
|
Jin SW, Mwimanzi FM, Mann JK, Bwana MB, Lee GQ, Brumme CJ, Hunt PW, Martin JN, Bangsberg DR, Ndung’u T, Brumme ZL, Brockman MA. Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5. PLoS Pathog 2020; 16:e1008813. [PMID: 32925973 PMCID: PMC7515180 DOI: 10.1371/journal.ppat.1008813] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 09/24/2020] [Accepted: 07/15/2020] [Indexed: 12/14/2022] Open
Abstract
HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.
Collapse
Affiliation(s)
- Steven W. Jin
- Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
| | | | - Jaclyn K. Mann
- HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
| | - Mwebesa Bosco Bwana
- Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda
| | - Guinevere Q. Lee
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | - Chanson J. Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
- Department of Medicine, University of British Columbia, Vancouver, Canada
| | - Peter W. Hunt
- School of Medicine, University of California, San Francisco, United States of America
| | - Jeff N. Martin
- School of Medicine, University of California, San Francisco, United States of America
| | - David R. Bangsberg
- School of Public Health, Oregon Health Science University, Portland, United States of America
| | - Thumbi Ndung’u
- HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
- Africa Health Research Institute, Durban, South Africa
- Ragon Institute of MGH, MIT, and Harvard University, Cambridge, United States of America
- Max Planck Institute for Infection Biology, Berlin, Germany
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - Zabrina L. Brumme
- Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | - Mark A. Brockman
- Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
- Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada
| |
Collapse
|
|
18
|
Acevedo-Saenz L, Perdomo-Celis F, Montoya CJ, Velilla PA. Polyfunctional CD8+ T-Cell Response to Autologous Peptides from Protease and Reverse Transcriptase of HIV-1 Clade B. Curr HIV Res 2020; 17:350-359. [PMID: 31622220 DOI: 10.2174/1570162x17666191017105910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/28/2019] [Accepted: 10/04/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. OBJECTIVE To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). METHODS By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. RESULTS Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1β. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. CONCLUSION Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.
Collapse
Affiliation(s)
- Liliana Acevedo-Saenz
- Grupo Inmunovirologia, Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia.,Grupo de Investigación Enfermería-CES, Facultad de Enfermería, Universidad CES, Medellin, Colombia
| | - Federico Perdomo-Celis
- Grupo Inmunovirologia, Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
| | - Carlos J Montoya
- Grupo Inmunovirologia, Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
| | - Paula A Velilla
- Grupo Inmunovirologia, Departamento de Microbiologia y Parasitologia, Facultad de Medicina, Universidad de Antioquia, Medellin, Colombia
| |
Collapse
|
|
19
|
Ahmed SF, Quadeer AA, Morales-Jimenez D, McKay MR. Sub-dominant principal components inform new vaccine targets for HIV Gag. Bioinformatics 2020; 35:3884-3889. [PMID: 31250884 DOI: 10.1093/bioinformatics/btz524] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 06/18/2019] [Accepted: 06/26/2019] [Indexed: 12/14/2022] Open
Abstract
MOTIVATION Patterns of mutational correlations, learnt from patient-derived sequences of human immunodeficiency virus (HIV) proteins, are informative of biochemically linked networks of interacting sites that may enable viral escape from the host immune system. Accurate identification of these networks is important for rationally designing vaccines which can effectively block immune escape pathways. Previous computational methods have partly identified such networks by examining the principal components (PCs) of the mutational correlation matrix of HIV Gag proteins. However, driven by a conservative approach, these methods analyze the few dominant (strongest) PCs, potentially missing information embedded within the sub-dominant (relatively weaker) ones that may be important for vaccine design. RESULTS By using sequence data for HIV Gag, complemented by model-based simulations, we revealed that certain networks of interacting sites that appear important for vaccine design purposes are not accurately reflected by the dominant PCs. Rather, these networks are encoded jointly by both dominant and sub-dominant PCs. By incorporating information from the sub-dominant PCs, we identified a network of interacting sites of HIV Gag that associated very strongly with viral control. Based on this network, we propose several new candidates for a potent T-cell-based HIV vaccine. AVAILABILITY AND IMPLEMENTATION Accession numbers of all sequences used and the source code scripts for all analysis and figures reported in this work are available online at https://github.com/faraz107/HIV-Gag-Immunogens. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
Collapse
Affiliation(s)
- Syed Faraz Ahmed
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Ahmed A Quadeer
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - David Morales-Jimenez
- Institute of Electronics, Communications and Information Technology, Queen's University Belfast, Belfast, UK
| | - Matthew R McKay
- Department of Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China.,Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| |
Collapse
|
|
20
|
Clinical and evolutionary consequences of HIV adaptation to HLA: implications for vaccine and cure. Curr Opin HIV AIDS 2020; 14:194-204. [PMID: 30925534 DOI: 10.1097/coh.0000000000000541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize recent advances in our understanding of HIV adaptation to human leukocyte antigen (HLA)-associated immune pressures and its relevance to HIV prevention and cure research. RECENT FINDINGS Recent research has confirmed that HLA is a major driver of individual and population-level HIV evolution, that HIV strains are adapting to the immunogenetic profiles of the different human ethnic groups in which they circulate, and that HIV adaptation has substantial clinical and immunologic consequences. As such, adaptation represents a major challenge to HIV prevention and cure. At the same time, there are opportunities: Studies of HIV adaptation are revealing why certain HLA alleles are protective in some populations and not others; they are identifying immunogenic viral epitopes that harbor high mutational barriers to escape, and they may help illuminate novel, vaccine-relevant HIV epitopes in regions where circulating adaptation is extensive. Elucidation of HLA-driven adapted and nonadapted viral forms in different human populations and HIV subtypes also renders 'personalized' immunogen selection, as a component of HIV cure strategies, conceptually feasible. SUMMARY Though adaptation represents a major challenge to HIV prevention and cure, achieving an in-depth understanding of this phenomenon can help move the design of such strategies forward.
Collapse
|
|
21
|
Currenti J, Chopra A, John M, Leary S, McKinnon E, Alves E, Pilkinton M, Smith R, Barnett L, McDonnell WJ, Lucas M, Noel F, Mallal S, Conrad JA, Kalams SA, Gaudieri S. Deep sequence analysis of HIV adaptation following vertical transmission reveals the impact of immune pressure on the evolution of HIV. PLoS Pathog 2019; 15:e1008177. [PMID: 31821379 PMCID: PMC6924686 DOI: 10.1371/journal.ppat.1008177] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 12/20/2019] [Accepted: 10/31/2019] [Indexed: 12/25/2022] Open
Abstract
Human immunodeficiency virus (HIV) can adapt to an individual’s T cell immune response via genomic mutations that affect antigen recognition and impact disease outcome. These viral adaptations are specific to the host’s human leucocyte antigen (HLA) alleles, as these molecules determine which peptides are presented to T cells. As HLA molecules are highly polymorphic at the population level, horizontal transmission events are most commonly between HLA-mismatched donor/recipient pairs, representing new immune selection environments for the transmitted virus. In this study, we utilised a deep sequencing approach to determine the HIV quasispecies in 26 mother-to-child transmission pairs where the potential for founder viruses to be pre-adapted is high due to the pairs being haplo-identical at HLA loci. This scenario allowed the assessment of specific HIV adaptations following transmission in either a non-selective immune environment, due to recipient HLA mismatched to original selecting HLA, or a selective immune environment, mediated by matched donor/recipient HLA. We show that the pattern of reversion or fixation of HIV adaptations following transmission provides insight into the replicative cost, and likely compensatory networks, associated with specific adaptations in vivo. Furthermore, although transmitted viruses were commonly heavily pre-adapted to the child’s HLA genotype, we found evidence of de novo post-transmission adaptation, representing new epitopes targeted by the child’s T cell response. High-resolution analysis of HIV adaptation is relevant when considering vaccine and cure strategies for individuals exposed to adapted viruses via transmission or reactivated from reservoirs. Highly mutable pathogens utilise genetic variations within T cell epitopes as a mechanism of immune escape (viral adaptation). The diversity of the human leucocyte antigen (HLA) molecules that present viral targets to T cells in human populations partially protects against rapid population-level accumulation of human immunodeficiency virus (HIV) adaptations through horizontal transmissions. In contrast, vertical transmissions occur between haplo-identical mother/child pairs, and potentially include adaptive changes through father-mother-child transmission, representing a pathway to complete pre-adaptation to HLA alleles in child hosts over only two transmission events. We utilised next-generation sequencing to examine HIV evolution in the unique setting of vertical HIV transmission. We predict the in vivo replicative cost and immune benefit of specific HIV adaptations that could be used to inform vaccine design and cure strategies to combat viral immune adaptation.
Collapse
Affiliation(s)
- Jennifer Currenti
- School of Human Sciences, University of Western Australia, Crawley, Western Australia, Australia
| | - Abha Chopra
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
| | - Mina John
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
- Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, Australia
| | - Shay Leary
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
| | - Elizabeth McKinnon
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
| | - Eric Alves
- School of Human Sciences, University of Western Australia, Crawley, Western Australia, Australia
| | - Mark Pilkinton
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Rita Smith
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Louise Barnett
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Wyatt J. McDonnell
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Michaela Lucas
- School of Medicine, University of Western Australia, Crawley, Western Australia, Australia
| | | | - Simon Mallal
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Joseph A. Conrad
- Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Spyros A. Kalams
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
| | - Silvana Gaudieri
- School of Human Sciences, University of Western Australia, Crawley, Western Australia, Australia
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America
- * E-mail:
| |
Collapse
|
|
22
|
Many human RNA viruses show extraordinarily stringent selective constraints on protein evolution. Proc Natl Acad Sci U S A 2019; 116:19009-19018. [PMID: 31484772 DOI: 10.1073/pnas.1907626116] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
How negative selection, positive selection, and population size contribute to the large variation in nucleotide substitution rates among RNA viruses remains unclear. Here, we studied the ratios of nonsynonymous-to-synonymous substitution rates (d N/d S) in protein-coding genes of human RNA and DNA viruses and mammals. Among the 21 RNA viruses studied, 18 showed a genome-average d N/d S from 0.01 to 0.10, indicating that over 90% of nonsynonymous mutations are eliminated by negative selection. Only HIV-1 showed a d N/d S (0.31) higher than that (0.22) in mammalian genes. By comparing the d N/d S values among genes in the same genome and among species or strains, we found that both positive selection and population size play significant roles in the d N/d S variation among genes and species. Indeed, even in flaviviruses and picornaviruses, which showed the lowest ratios among the 21 species studied, positive selection appears to have contributed significantly to d N/d S We found the view that positive selection occurs much more frequently in influenza A subtype H3N2 than subtype H1N1 holds only for the hemagglutinin and neuraminidase genes, but not for other genes. Moreover, we found no support for the view that vector-borne RNA viruses have lower d N/d S ratios than non-vector-borne viruses. In addition, we found a correlation between d N and d S, implying a correlation between d N and the mutation rate. Interestingly, only 2 of the 8 DNA viruses studied showed a d N/d S < 0.10, while 4 showed a d N/d S > 0.22. These observations increase our understanding of the mechanisms of RNA virus evolution.
Collapse
|
|
23
|
Adusei-Poku MA, Matsuoka S, Bonney EY, Abana CZ, Duker EO, Nii-Trebi NI, Ofori SB, Mizutani T, Ishizaka A, Shiino T, Kawana-Tachikawa A, Ishikawa K, Ampofo WK, Matano T. Human Leukocyte Antigen-Associated HIV-1 CRF02_AG gag and vif Polymorphisms in Ghana. Jpn J Infect Dis 2019; 72:374-380. [PMID: 31257246 DOI: 10.7883/yoken.jjid.2019.201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
In human immunodeficiency virus type-1 (HIV-1) infections, cytotoxic T-lymphocyte (CTL) responses targeting human leukocyte antigen (HLA)-restricted viral epitopes exert strong suppressive pressure on viral replication and frequently select for mutations resulting in viral escape from CTL recognition. Numerous data on these HLA-associated mutations in HIV-1 subtypes B and C have been amassed with few reports described in other subtypes. In the present study, we investigated the HLA-associated mutations in HIV-1 subtype CRF02_AG prevailing in Ghana, Western Africa. We determined viral gag sequences in 246 out of 324 HIV-1-infected Ghanaians. Phylogeny analysis revealed that 200 (81.3%) individuals were infected with HIV-1 CRF02_AG. Full gag and vif sequences were obtained from 199 and 138, respectively, out of the 200 individuals infected with CRF02_AG and subjected to determination of HLA-associated mutations. The analysis found HLA-associated HIV-1 CRF02_AG non-synonymous polymorphisms at 19 sites; 13 in gag and six in vif, including those that were newly determined. Generation of this data is an important contribution to our understanding of HIV-1 CRF02_AG and host T cell interaction.
Collapse
Affiliation(s)
- Mildred A Adusei-Poku
- Joint Research Center for Human Retrovirus Infection, Kumamoto University.,AIDS Research Center, National Institute of Infectious Diseases
| | - Saori Matsuoka
- AIDS Research Center, National Institute of Infectious Diseases
| | - Evelyn Y Bonney
- Noguchi Memorial Institute for Medical Research (NMIMR), University of Ghana
| | - Christopher Z Abana
- Noguchi Memorial Institute for Medical Research (NMIMR), University of Ghana
| | - Ewurabena O Duker
- Noguchi Memorial Institute for Medical Research (NMIMR), University of Ghana
| | - Nicholas I Nii-Trebi
- School of Biomedical and Allied Health, College of Health Sciences, University of Ghana
| | | | | | - Aya Ishizaka
- Institute of Medical Science, University of Tokyo
| | | | - Ai Kawana-Tachikawa
- Joint Research Center for Human Retrovirus Infection, Kumamoto University.,AIDS Research Center, National Institute of Infectious Diseases.,Institute of Medical Science, University of Tokyo
| | - Koichi Ishikawa
- AIDS Research Center, National Institute of Infectious Diseases
| | - William K Ampofo
- Noguchi Memorial Institute for Medical Research (NMIMR), University of Ghana
| | - Tetsuro Matano
- Joint Research Center for Human Retrovirus Infection, Kumamoto University.,AIDS Research Center, National Institute of Infectious Diseases.,Institute of Medical Science, University of Tokyo
| |
Collapse
|
|
24
|
Abstract
PURPOSE OF REVIEW A therapy that might cure HIV is a very important goal for the 30-40 million people living with HIV. Chimeric antigen receptor T cells have recently had remarkable success against certain leukemias, and there are reasons to believe they could be successful for HIV. This manuscript summarizes the published research on HIV CAR T cells and reviews the current anti-HIV chimeric antigen receptor strategies. RECENT FINDINGS Research on anti-HIV chimeric antigen receptor T cells has been going on for at least the last 25 years. First- and second-generation anti-HIV chimeric antigen receptors have been developed. First-generation anti-HIV chimeric antigen receptors were studied in clinical trials more than 15 years ago, but did not have meaningful clinical efficacy. There are some reasons to be optimistic about second-generation anti-HIV chimeric antigen receptor T cells, but they have not yet been tested in vivo.
Collapse
Affiliation(s)
- Thor A Wagner
- Seattle Children's Research Institute, 1900 Ninth Ave, 8th Floor, Seattle, WA, 98101, USA. .,University of Washington, 1959 NE Pacific St., Box 356320, Seattle, WA, 98195-6320, USA.
| |
Collapse
|
|
25
|
Resistance Analysis of Bictegravir-Emtricitabine-Tenofovir Alafenamide in HIV-1 Treatment-Naive Patients through 48 Weeks. Antimicrob Agents Chemother 2019; 63:AAC.02533-18. [PMID: 30803969 DOI: 10.1128/aac.02533-18] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 02/17/2019] [Indexed: 11/20/2022] Open
Abstract
In clinical studies GS-US-380-1489 (study 1489) and GS-US-380-1490 (study 1490), bictegravir-emtricitabine-tenofovir alafenamide (B-F-TAF), dolutegravir-abacavir-lamivudine (DTG-ABC-3TC), and dolutegravir plus emtricitabine-tenofovir alafenamide (DTG+F-TAF) treatment achieved high rates of virologic suppression in HIV-1 treatment-naive participants through week 48. Preexisting primary drug resistance was present at levels of 1.3% integrase strand transfer inhibitor resistance (INSTI-R), 2.7% nucleoside reverse transcriptase inhibitor resistance (NRTI-R), 14.1% nonnucleoside reverse transcriptase inhibitor resistance (NNRTI-R), and 3.5% protease inhibitor resistance (PI-R) in the 1,274 participants from these studies. These mutations did not affect treatment outcomes. Resistance analyses in 13 virologic failures found no emergent resistance to study drugs.
Collapse
|
|
26
|
Shadabi E, Liang B, Plummer F, Luo M. Identification and Characterization of Positively Selected Mutations in Nef of Four HIV-1 Major Subtypes from Los Alamos National Laboratory. Curr HIV Res 2019; 16:130-142. [PMID: 29600767 DOI: 10.2174/1570162x16666180330140807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 03/07/2018] [Accepted: 03/20/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND Human immunodeficiency virus-1 (HIV-1) mutates rapidly to escape host immune pressure. This results in the generation of positively selected mutations (PSM) throughout the viral genome. Escape mutations in Nef, one of the accessory proteins of HIV-1, which plays an important role in viral pathogenicity have previously been identified in several large cohort studies, but the evolution of PSMs overtime in various HIV-1 subtypes remains unknown. METHODS 161 clade A1, 3093 clade B, 647 clade C and 115 clade D HIV-1 nef sequences were obtained from the HIV Database of Los Alamos National Laboratory and aligned using MEGA 6.0. The sequences from each clade were grouped based on the year of collection. Quasi analysis was used to identify PSMs and the number and locations of PSMs were compared among different subtypes. RESULTS PSMs for all four subtypes were distributed across the sequence of Nef, and conserved residues F90, W113, PxxPxR (a.a 72-77) remain unaltered overtime. The frequency of PSMs was stable among subtype B sequences but increased overtime for other subtypes. Phylogenetic analysis shows that sequences containing PSMs tend to cluster together at both inter and intra- subtype levels. CONCLUSION Identification of PSMs and their changes overtime within various subtypes of HIV-1 is important in defining global viral evolutionary patterns that can provide insights for designing therapeutic strategies.
Collapse
Affiliation(s)
- Elnaz Shadabi
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Binhua Liang
- JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Frank Plummer
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ma Luo
- Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada.,JC Wilt Infectious Disease Research Centre, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| |
Collapse
|
|
27
|
Rosás-Umbert M, Llano A, Bellido R, Olvera A, Ruiz-Riol M, Rocafort M, Fernández MA, Cobarsi P, Crespo M, Dorrell L, Del Romero J, Alcami J, Paredes R, Brander C, Mothe B. Mechanisms of Abrupt Loss of Virus Control in a Cohort of Previous HIV Controllers. J Virol 2019; 93:e01436-18. [PMID: 30487276 PMCID: PMC6363998 DOI: 10.1128/jvi.01436-18] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/16/2018] [Indexed: 12/19/2022] Open
Abstract
Elite and viremic HIV controllers are able to control their HIV infection and maintain undetectable or low-level viremia in the absence of antiretroviral treatment. Despite extensive studies, the immune factors responsible for such exclusive control remain poorly defined. We identified a cohort of 14 HIV controllers that suffered an abrupt loss of HIV control (LoC) to investigate possible mechanisms and virological and immunological events related to the sudden loss of control. The in-depth analysis of these subjects involved the study of cell tropism of circulating virus, evidence for HIV superinfection, cellular immune responses to HIV, as well as an examination of viral adaptation to host immunity by Gag sequencing. Our data demonstrate that a poor capacity of T cells to mediate in vitro viral suppression, even in the context of protective HLA alleles, predicts a loss of viral control. In addition, the data suggest that inefficient viral control may be explained by an increase of CD8 T-cell activation and exhaustion before LoC. Furthermore, we detected a switch from C5- to X4-tropic viruses in 4 individuals after loss of control, suggesting that tropism shift might also contribute to disease progression in HIV controllers. The significantly reduced inhibition of in vitro viral replication and increased expression of activation and exhaustion markers preceding the abrupt loss of viral control may help identify untreated HIV controllers that are at risk of losing control and may offer a useful tool for monitoring individuals during treatment interruption phases in therapeutic vaccine trials.IMPORTANCE A few individuals can control HIV infection without the need for antiretroviral treatment and are referred to as HIV controllers. We have studied HIV controllers who suddenly lose this ability and present with high in vivo viral replication and decays in their CD4+ T-cell counts to identify potential immune and virological factors that were responsible for initial virus control. We identify in vitro-determined reductions in the ability of CD8 T cells to suppress viral control and the presence of PD-1-expressing CD8+ T cells with a naive immune phenotype as potential predictors of in vivo loss of virus control. The findings could be important for the clinical management of HIV controller individuals, and it may offer an important tool to anticipate viral rebound in individuals in clinical studies that include combination antiretroviral therapy (cART) treatment interruptions and which, if not treated quickly, could pose a significant risk to the trial participants.
Collapse
Affiliation(s)
- Miriam Rosás-Umbert
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Anuska Llano
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Rocío Bellido
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Alex Olvera
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Marta Ruiz-Riol
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Muntsa Rocafort
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Marco A Fernández
- Flow Cytometry Facility, Health Sciences Research Institute Germans Trias i Pujol, Badalona, Spain
| | - Patricia Cobarsi
- HIV Unit, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Manel Crespo
- Infectious Diseases Unit, Internal Medicine Department, Complexo Hospitalario Universitario de Vigo, IIS Galicia Sur, Spain
| | - Lucy Dorrell
- Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | - José Alcami
- Instituto de Salud Carlos III, Madrid, Spain
| | - Roger Paredes
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- HIV Unit, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- University of Vic and Central Catalonia, UVIC-UCC, Vic, Spain
| | - Christian Brander
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- University of Vic and Central Catalonia, UVIC-UCC, Vic, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- AELIX Therapeutics, Barcelona, Spain
| | - Beatriz Mothe
- IrsiCaixa AIDS Research Institute-HIVACAT, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- HIV Unit, Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- University of Vic and Central Catalonia, UVIC-UCC, Vic, Spain
| |
Collapse
|
|
28
|
BRUMME ZL, SUDDERUDDIN H, ZIEMNIAK C, LUZURIAGA K, JONES BR, JOY JB, CUNNINGHAM CK, GREENOUGH T, PERSAUD D. Genetic complexity in the replication-competent latent HIV reservoir increases with untreated infection duration in infected youth. AIDS 2019; 33:211-218. [PMID: 30325763 PMCID: PMC6298800 DOI: 10.1097/qad.0000000000002045] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE Timely initiation of combination antiretroviral therapy (ART) limits latent HIV reservoir size and should also limit reservoir genetic complexity. However, the relationship between these two factors remains unclear, particularly among HIV-infected youth. DESIGN Retrospective analysis of replication-competent latent HIV clones serially isolated by limiting-dilution culture from resting CD4 T-cell reservoirs from ART-suppressed, young adult participants of a historic phase I therapeutic vaccine trial (PACTG/IMPAACT-P1059). METHODS Replication-competent latent HIV clones isolated from resting CD4 T cells of four perinatally and 10 nonperinatally infected young adults (average 22 versus 6 years uncontrolled infection, respectively) were sequenced in Pol and Nef. Within-host HIV sequence datasets were characterized with respect to their genetic diversity and inferred immune escape mutation burden. RESULTS Although participants were comparable in terms of sociodemographic and HIV sampling characteristics (e.g. on average, a mean 17 Pol sequences were recovered at five timepoints over up to 70 weeks) and the length of ART suppression at study entry (average 3 years), replication-competent HIV reservoir size, genetic diversity, immune escape mutation burden and variant complexity were significantly higher among the perinatally infected participants who experienced longer durations of uncontrolled viremia. Nevertheless, viral sequences inferred to retain susceptibility to host cellular immune responses were detected in all participants, irrespective of uncontrolled viremia duration. CONCLUSION HIV elimination in late-suppressed youth may be doubly challenged by larger and more genetically complex reservoirs. Strategies that integrate host and viral genetic complexity to achieve HIV remission or cure may merit consideration in such cases.
Collapse
Affiliation(s)
- Zabrina L. BRUMME
- Faculty of Health Sciences, Simon Fraser University, Burnaby, BC Canada
- BC Centre for Excellence in HIV/AIDS, Vancouver BC, Canada
| | | | | | | | - Bradley R. JONES
- BC Centre for Excellence in HIV/AIDS, Vancouver BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC Canada
| | - Jeffrey B. JOY
- BC Centre for Excellence in HIV/AIDS, Vancouver BC, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC Canada
| | | | | | | |
Collapse
|
|
29
|
Borzooee F, Joris KD, Grant MD, Larijani M. APOBEC3G Regulation of the Evolutionary Race Between Adaptive Immunity and Viral Immune Escape Is Deeply Imprinted in the HIV Genome. Front Immunol 2019; 9:3032. [PMID: 30687306 PMCID: PMC6338068 DOI: 10.3389/fimmu.2018.03032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 12/07/2018] [Indexed: 12/16/2022] Open
Abstract
APOBEC3G (A3G) is a host enzyme that mutates the genomes of retroviruses like HIV. Since A3G is expressed pre-infection, it has classically been considered an agent of innate immunity. We and others previously showed that the impact of A3G-induced mutations on the HIV genome extends to adaptive immunity also, by generating cytotoxic T cell (CTL) escape mutations. Accordingly, HIV genomic sequences encoding CTL epitopes often contain A3G-mutable “hotspot” sequence motifs, presumably to channel A3G action toward CTL escape. Here, we studied the depths and consequences of this apparent viral genome co-evolution with A3G. We identified all potential CTL epitopes in Gag, Pol, Env, and Nef restricted to several HLA class I alleles. We simulated A3G-induced mutations within CTL epitope-encoding sequences, and flanking regions. From the immune recognition perspective, we analyzed how A3G-driven mutations are predicted to impact CTL-epitope generation through modulating proteasomal processing and HLA class I binding. We found that A3G mutations were most often predicted to result in diminishing/abolishing HLA-binding affinity of peptide epitopes. From the viral genome evolution perspective, we evaluated enrichment of A3G hotspots at sequences encoding CTL epitopes and included control sequences in which the HIV genome was randomly shuffled. We found that sequences encoding immunogenic epitopes exhibited a selective enrichment of A3G hotspots, which were strongly biased to translate to non-synonymous amino acid substitutions. When superimposed on the known mutational gradient across the entire length of the HIV genome, we observed a gradient of A3G hotspot enrichment, and an HLA-specific pattern of the potential of A3G hotspots to lead to CTL escape mutations. These data illuminate the depths and extent of the co-evolution of the viral genome to subvert the host mutator A3G.
Collapse
Affiliation(s)
- Faezeh Borzooee
- Immunology and Infectious Diseases Program, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Krista D Joris
- Immunology and Infectious Diseases Program, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Michael D Grant
- Immunology and Infectious Diseases Program, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| | - Mani Larijani
- Immunology and Infectious Diseases Program, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada
| |
Collapse
|
|
30
|
Kinloch NN, Lee GQ, Carlson JM, Jin SW, Brumme CJ, Byakwaga H, Muzoora C, Bwana MB, Cobarrubias KD, Hunt PW, Martin JN, Carrington M, Bangsberg DR, Harrigan PR, Brockman MA, Brumme ZL. Genotypic and Mechanistic Characterization of Subtype-Specific HIV Adaptation to Host Cellular Immunity. J Virol 2019; 93:e01502-18. [PMID: 30305354 PMCID: PMC6288327 DOI: 10.1128/jvi.01502-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 09/28/2018] [Indexed: 11/20/2022] Open
Abstract
The extent to which viral genetic context influences HIV adaptation to human leukocyte antigen (HLA) class I-restricted immune pressures remains incompletely understood. The Ugandan HIV epidemic, where major pandemic group M subtypes A1 and D cocirculate in a single host population, provides an opportunity to investigate this question. We characterized plasma HIV RNA gag, pol, and nef sequences, along with host HLA genotypes, in 464 antiretroviral-naive individuals chronically infected with HIV subtype A1 or D. Using phylogenetically informed statistical approaches, we identified HLA-associated polymorphisms and formally compared their strengths of selection between viral subtypes. A substantial number (32%) of HLA-associated polymorphisms identified in subtype A1 and/or D had previously been reported in subtype B, C, and/or circulating recombinant form 01_AE (CRF01_AE), confirming the shared nature of many HLA-driven escape pathways regardless of viral genetic context. Nevertheless, 34% of the identified HLA-associated polymorphisms were significantly differentially selected between subtypes A1 and D. Experimental investigation of select examples of subtype-specific escape revealed distinct underlying mechanisms with important implications for vaccine design: whereas some were attributable to subtype-specific sequence variation that influenced epitope-HLA binding, others were attributable to differential mutational barriers to immune escape. Overall, our results confirm that HIV genetic context is a key modulator of viral adaptation to host cellular immunity and highlight the power of combined bioinformatic and mechanistic studies, paired with knowledge of epitope immunogenicity, to identify appropriate viral regions for inclusion in subtype-specific and universal HIV vaccine strategies.IMPORTANCE The identification of HIV polymorphisms reproducibly selected under pressure by specific HLA alleles and the elucidation of their impact on viral function can help identify immunogenic viral regions where immune escape incurs a fitness cost. However, our knowledge of HLA-driven escape pathways and their functional costs is largely limited to HIV subtype B and, to a lesser extent, subtype C. Our study represents the first characterization of HLA-driven adaptation pathways in HIV subtypes A1 and D, which dominate in East Africa, and the first statistically rigorous characterization of differential HLA-driven escape across viral subtypes. The results support a considerable impact of viral genetic context on HIV adaptation to host HLA, where HIV subtype-specific sequence variation influences both epitope-HLA binding and the fitness costs of escape. Integrated bioinformatic and mechanistic characterization of these and other instances of differential escape could aid rational cytotoxic T-lymphocyte-based vaccine immunogen selection for both subtype-specific and universal HIV vaccines.
Collapse
Affiliation(s)
- Natalie N Kinloch
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Guinevere Q Lee
- Ragon Institute of Massachusetts General Hospital, MIT and Harvard, Cambridge, Massachusetts, USA
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | | | - Steven W Jin
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Chanson J Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Helen Byakwaga
- Mbarara University of Science and Technology, Mbarara, Uganda
- University of California, San Francisco, San Francisco, California, USA
| | - Conrad Muzoora
- Mbarara University of Science and Technology, Mbarara, Uganda
| | - Mwebesa B Bwana
- Mbarara University of Science and Technology, Mbarara, Uganda
| | - Kyle D Cobarrubias
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Peter W Hunt
- University of California, San Francisco, San Francisco, California, USA
| | - Jeff N Martin
- University of California, San Francisco, San Francisco, California, USA
| | - Mary Carrington
- Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - David R Bangsberg
- Oregon Health and Science University-Portland State University School of Public Health, Portland, Oregon, USA
| | - P Richard Harrigan
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mark A Brockman
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| | - Zabrina L Brumme
- Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada
| |
Collapse
|
|
31
|
Takahashi N, Matsuoka S, Thi Minh TT, Ba HP, Naruse TK, Kimura A, Shiino T, Kawana-Tachikawa A, Ishikawa K, Matano T, Nguyen Thi LA. Human leukocyte antigen-associated gag and nef polymorphisms in HIV-1 subtype A/E-infected individuals in Vietnam. Microbes Infect 2018; 21:113-118. [PMID: 30385305 DOI: 10.1016/j.micinf.2018.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 09/29/2018] [Accepted: 10/01/2018] [Indexed: 10/28/2022]
Abstract
Numbers of HLA-associated polymorphisms have been reported on HIV-1 subtypes B and C, but few on other subtypes. Here, we analyzed HLA-associated gag and nef polymorphisms in HIV-1 subtype A/E prevalent in Vietnam. We determined HLA-A, B and C genotypes in 179 HIV-1-infected Vietnamese by next generation sequencing and analyzed proviral genome sequences in 144 of them, showing that 142 of the 144 were subtype A/E. Analysis revealed HLA-associated subtype A/E gag and nef polymorphisms at nineteen residues including those newly determined. Accumulation of these data would contribute to our understanding of HIV-1 subtype A/E and host immune interaction.
Collapse
Affiliation(s)
- Naofumi Takahashi
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Saori Matsuoka
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Tam Tran Thi Minh
- Center of BioMedical Research, National Institute of Hygiene and Epidemiology, No.1 Yersin Street, Hanoi, Viet Nam
| | - Hien Pham Ba
- Dong Da General Hospital, No. 192, Nguyen Luong Bang Street, Hanoi, Viet Nam
| | - Taeko K Naruse
- Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Akinori Kimura
- Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Teiichiro Shiino
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Ai Kawana-Tachikawa
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Koichi Ishikawa
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan
| | - Tetsuro Matano
- AIDS Research Center, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan; The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
| | - Lan Anh Nguyen Thi
- Center of BioMedical Research, National Institute of Hygiene and Epidemiology, No.1 Yersin Street, Hanoi, Viet Nam.
| |
Collapse
|
|
32
|
Pol-Driven Replicative Capacity Impacts Disease Progression in HIV-1 Subtype C Infection. J Virol 2018; 92:JVI.00811-18. [PMID: 29997209 DOI: 10.1128/jvi.00811-18] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 06/20/2018] [Indexed: 01/31/2023] Open
Abstract
CD8+ T cell-mediated escape mutations in Gag can reduce HIV-1 replication capacity (RC) and alter disease progression, but less is known about immune-mediated attenuation in other HIV-1 proteins. We generated 487 recombinant viruses encoding RT-integrase from individuals with chronic (n = 406) and recent (n = 81) HIV-1 subtype C infection and measured their in vitro RC using a green fluorescent protein (GFP) reporter T cell assay. In recently infected individuals, reverse transcriptase (RT)-integrase-driven RC correlated significantly with viral load set point (r = 0.25; P = 0.03) and CD4+ T cell decline (P = 0.013). Moreover, significant associations between RT integrase-driven RC and viral load (r = 0.28; P < 0.0001) and CD4+ T cell count (r = -0.29; P < 0.0001) remained in chronic infection. In early HIV infection, host expression of the protective HLA-B*81 allele was associated with lower RC (P = 0.05), as was expression of HLA-B*07 (P = 0.02), suggesting early immune-driven attenuation of RT-integrase by these alleles. In chronic infection, HLA-A*30:09 (in linkage disequilibrium with HLA-B*81) was significantly associated with lower RC (P = 0.05), and all 6 HLA-B alleles with the lowest RC measurements represented protective alleles, consistent with long-term effects of host immune pressures on lowering RT-integrase RC. The polymorphisms V241I, I257V, P272K, and E297K in reverse transcriptase and I201V in integrase, all relatively uncommon polymorphisms occurring in or adjacent to optimally described HLA-restricted cytotoxic T-lymphocyte epitopes, were associated with reduced RC. Together, our data suggest that RT-integrase-driven RC is clinically relevant and provide evidence that immune-driven selection of mutations in RT-integrase can compromise RC.IMPORTANCE Identification of viral mutations that compromise HIV's ability to replicate may aid rational vaccine design. However, while certain escape mutations in Gag have been shown to reduce HIV replication and influence clinical progression, less is known about the consequences of mutations that naturally arise in other HIV proteins. Pol is a highly conserved protein, but the impact of Pol function on HIV disease progression is not well defined. Here, we generated recombinant viruses using the RT-integrase region of Pol derived from HIV-1C-infected individuals with recent and chronic infection and measured their ability to replicate in vitro We demonstrate that RT-integrase-driven replication ability significantly impacts HIV disease progression. We further show evidence of immune-mediated attenuation in RT-integrase and identify specific polymorphisms in RT-integrase that significantly decrease HIV-1 replication ability, suggesting which Pol epitopes could be explored in vaccine development.
Collapse
|
|
33
|
Abstract
Supplemental Digital Content is available in the text Objective: HIV incidence in the Canadian province of Saskatchewan, where Indigenous persons make up 80% of those infected, are among the highest on the continent. Reports of accelerated HIV progression, associated with carriage of certain human leukocyte antigen (HLA) alleles (including the typically protective HLA-B∗51) have also emerged from the region. Given that acquisition of HIV preadapted to host HLA negatively impacts clinical outcome, we hypothesized that HIV-host adaptation may be elevated in Saskatchewan. Design: Comparative analysis of population-level HIV sequence datasets from Saskatchewan and elsewhere in Canada/USA. Methods: We analyzed 1144 HIV subtype B Pol sequences collected in Saskatchewan between 2000 and 2016, comprising ∼65% of cumulative provincial HIV cases, for the presence of 70 HLA-associated Pol mutations. Sequences from British Columbia (N = 6525) and elsewhere in Canada/USA (N = 6517) were used for comparison. HIV adaptation levels to 34 HLA alleles were also computed. Putative HIV transmission clusters were identified, and the prevalence of HLA-associated adaptations within and outside these clusters was investigated. Results: Analyses confirmed significantly elevated and temporally increasing levels of HIV adaptation to commonly expressed HLA alleles, in particular B∗51. Notably, HLA-adapted HIV strains were significantly enriched among phylogenetic clusters in Saskatchewan. Conclusion: Extensive circulating HIV adaptation to HLA in Saskatchewan provides a plausible explanation for accelerated progression, while enrichment of adapted variants in phylogenetic clusters suggests they are being widely transmitted. Results highlight the utility of Pol sequences, routinely collected for drug resistance monitoring, for surveillance of HIV-host adaptation, and underscore the urgent need to expand HIV prevention and treatment programmes in Saskatchewan.
Collapse
|
|
34
|
Valenzuela-Ponce H, Alva-Hernández S, Garrido-Rodríguez D, Soto-Nava M, García-Téllez T, Escamilla-Gómez T, García-Morales C, Quiroz-Morales VS, Tapia-Trejo D, Del Arenal-Sánchez S, Prado-Galbarro FJ, Hernández-Juan R, Rodríguez-Aguirre E, Murakami-Ogasawara A, Mejía-Villatoro C, Escobar-Urias IY, Pinzón-Meza R, Pascale JM, Zaldivar Y, Porras-Cortés G, Quant-Durán C, Lorenzana I, Meza RI, Palou EY, Manzanero M, Cedillos RA, Aláez C, Brockman MA, Harrigan PR, Brumme CJ, Brumme ZL, Ávila-Ríos S, Reyes-Terán G. Novel HLA class I associations with HIV-1 control in a unique genetically admixed population. Sci Rep 2018; 8:6111. [PMID: 29666450 PMCID: PMC5904102 DOI: 10.1038/s41598-018-23849-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 03/21/2018] [Indexed: 12/26/2022] Open
Abstract
Associations between HLA class I alleles and HIV progression in populations exhibiting Amerindian and Caucasian genetic admixture remain understudied. Using univariable and multivariable analyses we evaluated HLA associations with five HIV clinical parameters in 3,213 HIV clade B-infected, ART-naïve individuals from Mexico and Central America (MEX/CAM cohort). A Canadian cohort (HOMER, n = 1622) was used for comparison. As expected, HLA allele frequencies in MEX/CAM and HOMER differed markedly. In MEX/CAM, 13 HLA-A, 24 HLA-B, and 14 HLA-C alleles were significantly associated with at least one clinical parameter. These included previously described protective (e.g. B*27:05, B*57:01/02/03 and B*58:01) and risk (e.g. B*35:02) alleles, as well as novel ones (e.g. A*03:01, B*15:39 and B*39:02 identified as protective, and A*68:03/05, B*15:30, B*35:12/14, B*39:01/06, B*39:05~C*07:02, and B*40:01~C*03:04 identified as risk). Interestingly, both protective (e.g. B*39:02) and risk (e.g. B*39:01/05/06) subtypes were identified within the common and genetically diverse HLA-B*39 allele group, characteristic to Amerindian populations. While HLA-HIV associations identified in MEX and CAM separately were similar overall (Spearman's rho = 0.33, p = 0.03), region-specific associations were also noted. The identification of both canonical and novel HLA/HIV associations provides a first step towards improved understanding of HIV immune control among unique and understudied Mestizo populations.
Collapse
Affiliation(s)
- Humberto Valenzuela-Ponce
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Selma Alva-Hernández
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Daniela Garrido-Rodríguez
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Maribel Soto-Nava
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Thalía García-Téllez
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico.,Institut Pasteur, Unité HIV, Inflammation and Persistence, Paris, France
| | - Tania Escamilla-Gómez
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Claudia García-Morales
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | | | - Daniela Tapia-Trejo
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Silvia Del Arenal-Sánchez
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | | | - Ramón Hernández-Juan
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Edna Rodríguez-Aguirre
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | - Akio Murakami-Ogasawara
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico
| | | | | | | | | | - Yamitzel Zaldivar
- Instituto Conmemorativo Gorgas de Estudios de la Salud, Panama City, Panama
| | | | | | - Ivette Lorenzana
- Universidad Nacional Autónoma de Honduras, Tegucigalpa, Honduras
| | - Rita I Meza
- Honduras HIV National Laboratory, Tegucigalpa, Honduras
| | - Elsa Y Palou
- Hospital Escuela Universitario, Tegucigalpa, Honduras
| | | | | | - Carmen Aláez
- National Institute of Genomic Medicine, Translational Medicine Laboratory, Mexico City, Mexico
| | - Mark A Brockman
- Simon Fraser University, Faculty of Health Sciences, Burnaby, Canada.,British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | | | - Chanson J Brumme
- British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | - Zabrina L Brumme
- Simon Fraser University, Faculty of Health Sciences, Burnaby, Canada.,British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
| | - Santiago Ávila-Ríos
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico.
| | - Gustavo Reyes-Terán
- National Institute of Respiratory Diseases, CIENI Center for Research in Infectious Diseases, Mexico City, Mexico.
| | | |
Collapse
|
|
35
|
Weaker HLA Footprints on HIV in the Unique and Highly Genetically Admixed Host Population of Mexico. J Virol 2018; 92:JVI.01128-17. [PMID: 29093100 PMCID: PMC5752930 DOI: 10.1128/jvi.01128-17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/27/2017] [Indexed: 01/24/2023] Open
Abstract
HIV circumvents HLA class I-restricted CD8+ T-cell responses through selection of escape mutations that leave characteristic mutational “footprints,” also known as HLA-associated polymorphisms (HAPs), on HIV sequences at the population level. While many HLA footprints are universal across HIV subtypes and human populations, others can be region specific as a result of the unique immunogenetic background of each host population. Using a published probabilistic phylogenetically informed model, we compared HAPs in HIV Gag and Pol (PR-RT) in 1,612 subtype B-infected, antiretroviral treatment-naive individuals from Mexico and 1,641 individuals from Canada/United States. A total of 252 HLA class I allele subtypes were represented, including 140 observed in both cohorts, 67 unique to Mexico, and 45 unique to Canada/United States. At the predefined statistical threshold of a q value of <0.2, 358 HAPs (201 in Gag, 157 in PR-RT) were identified in Mexico, while 905 (534 in Gag and 371 in PR-RT) were identified in Canada/United States. HAPs identified in Mexico included both canonical HLA-associated escape pathways and novel associations, in particular with HLA alleles enriched in Amerindian and mestizo populations. Remarkably, HLA footprints on HIV in Mexico were not only fewer but also, on average, significantly weaker than those in Canada/United States, although some exceptions were noted. Moreover, exploratory analyses suggested that the weaker HLA footprint on HIV in Mexico may be due, at least in part, to weaker and/or less reproducible HLA-mediated immune pressures on HIV in this population. The implications of these differences for natural and vaccine-induced anti-HIV immunity merit further investigation. IMPORTANCE HLA footprints on HIV identify viral regions under intense and consistent pressure by HLA-restricted immune responses and the common mutational pathways that HIV uses to evade them. In particular, HLA footprints can identify novel immunogenic regions and/or epitopes targeted by understudied HLA alleles; moreover, comparative analyses across immunogenetically distinct populations can illuminate the extent to which HIV immunogenic regions and escape pathways are shared versus population-specific pathways, information which can in turn inform the design of universal or geographically tailored HIV vaccines. We compared HLA-associated footprints on HIV in two immunogenetically distinct North American populations, those of Mexico and Canada/United States. We identify both shared and population-specific pathways of HIV adaptation but also make the surprising observation that HLA footprints on HIV in Mexico overall are fewer and weaker than those in Canada/United States, raising the possibility that HLA-restricted antiviral immune responses in Mexico are weaker, and/or escape pathways somewhat less consistent, than those in other populations.
Collapse
|
|
36
|
Resistance of Major Histocompatibility Complex Class B (MHC-B) to Nef-Mediated Downregulation Relative to that of MHC-A Is Conserved among Primate Lentiviruses and Influences Antiviral T Cell Responses in HIV-1-Infected Individuals. J Virol 2017; 92:JVI.01409-17. [PMID: 29046444 DOI: 10.1128/jvi.01409-17] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 10/03/2017] [Indexed: 12/19/2022] Open
Abstract
Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n = 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+ effector cells in vitro Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.IMPORTANCE Primate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to the MHC-B downregulation function in HIV-1 subtype C and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionarily conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.
Collapse
|
|
37
|
Effects of Mutations on Replicative Fitness and Major Histocompatibility Complex Class I Binding Affinity Are Among the Determinants Underlying Cytotoxic-T-Lymphocyte Escape of HIV-1 Gag Epitopes. mBio 2017; 8:mBio.01050-17. [PMID: 29184023 PMCID: PMC5705913 DOI: 10.1128/mbio.01050-17] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Certain “protective” major histocompatibility complex class I (MHC-I) alleles, such as B*57 and B*27, are associated with long-term control of HIV-1 in vivo mediated by the CD8+ cytotoxic-T-lymphocyte (CTL) response. However, the mechanism of such superior protection is not fully understood. Here we combined high-throughput fitness profiling of mutations in HIV-1 Gag, in silico prediction of MHC-peptide binding affinity, and analysis of intraperson virus evolution to systematically compare differences with respect to CTL escape mutations between epitopes targeted by protective MHC-I alleles and those targeted by nonprotective MHC-I alleles. We observed that the effects of mutations on both viral replication and MHC-I binding affinity are among the determinants of CTL escape. Mutations in Gag epitopes presented by protective MHC-I alleles are associated with significantly higher fitness cost and lower reductions in binding affinity with respect to MHC-I. A linear regression model accounting for the effect of mutations on both viral replicative capacity and MHC-I binding can explain the protective efficacy of MHC-I alleles. Finally, we found a consistent pattern in the evolution of Gag epitopes in long-term nonprogressors versus progressors. Overall, our results suggest that certain protective MHC-I alleles allow superior control of HIV-1 by targeting epitopes where mutations typically incur high fitness costs and small reductions in MHC-I binding affinity. Understanding the mechanism of viral control achieved in long-term nonprogressors with protective HLA alleles provides insights for developing functional cure of HIV infection. Through the characterization of CTL escape mutations in infected persons, previous researchers hypothesized that protective alleles target epitopes where escape mutations significantly reduce viral replicative capacity. However, these studies were usually limited to a few mutations observed in vivo. Here we utilized our recently developed high-throughput fitness profiling method to quantitatively measure the fitness of mutations across the entirety of HIV-1 Gag. The data enabled us to integrate the results with in silico prediction of MHC-peptide binding affinity and analysis of intraperson virus evolution to systematically determine the differences in CTL escape mutations between epitopes targeted by protective HLA alleles and those targeted by nonprotective HLA alleles. We observed that the effects of Gag epitope mutations on HIV replicative fitness and MHC-I binding affinity are among the major determinants of CTL escape.
Collapse
|
|
38
|
Rosás-Umbert M, Mothe B, Noguera-Julian M, Bellido R, Puertas MC, Carrillo J, Rodriguez C, Perez-Alvarez N, Cobarsí P, Gomez CE, Esteban M, Jímenez JL, García F, Blanco J, Martinez-Picado J, Paredes R, Brander C. Virological and immunological outcome of treatment interruption in HIV-1-infected subjects vaccinated with MVA-B. PLoS One 2017; 12:e0184929. [PMID: 28953921 PMCID: PMC5617163 DOI: 10.1371/journal.pone.0184929] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 08/13/2017] [Indexed: 01/02/2023] Open
Abstract
The most relevant endpoint in therapeutic HIV vaccination is the assessment of time to viral rebound or duration of sustained control of low-level viremia upon cART treatment cessation. Structured treatment interruptions (STI) are however not without risk to the patient and reliable predictors of viral rebound/control after therapeutic HIV-1 vaccination are urgently needed to ensure patient safety and guide therapeutic vaccine development. Here, we integrated immunological and virological parameters together with viral rebound dynamics after STI in a phase I therapeutic vaccine trial of a polyvalent MVA-B vaccine candidate to define predictors of viral control. Clinical parameters, proviral DNA, host HLA genetics and measures of humoral and cellular immunity were evaluated. A sieve effect analysis was conducted comparing pre-treatment viral sequences to breakthrough viruses after STI. Our results show that a reduced proviral HIV-1 DNA at study entry was independently associated with two virological parameters, delayed HIV-1 RNA rebound (p = 0.029) and lower peak viremia after treatment cessation (p = 0.019). Reduced peak viremia was also positively correlated with a decreased number of HLA class I allele associated polymorphisms in Gag sequences in the rebounding virus population (p = 0.012). Our findings suggest that proviral DNA levels and the number of HLA-associated Gag polymorphisms may have an impact on the clinical outcome of STI. Incorporation of these parameters in future therapeutic vaccine trials may guide refined immunogen design and help conduct safer STI approaches.
Collapse
Affiliation(s)
- Miriam Rosás-Umbert
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Beatriz Mothe
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- “Lluita contra la SIDA” Foundation, Hospital Germans Trias i Pujol, Badalona, Spain
- University of VIC and Central Catalonia, Vic, Spain
| | - Marc Noguera-Julian
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- University of VIC and Central Catalonia, Vic, Spain
| | - Rocío Bellido
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Maria C. Puertas
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Jorge Carrillo
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
| | - C. Rodriguez
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Núria Perez-Alvarez
- “Lluita contra la SIDA” Foundation, Hospital Germans Trias i Pujol, Badalona, Spain
- Universitat Politecnica de Catalunya, Barcelona, Spain
| | - Patricia Cobarsí
- “Lluita contra la SIDA” Foundation, Hospital Germans Trias i Pujol, Badalona, Spain
| | | | | | | | - Felipe García
- Hospital Clinic–HIVACAT, IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Julià Blanco
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- University of VIC and Central Catalonia, Vic, Spain
- Health Sciences Research Institute Germans Trias i Pujol, IGTP, Badalona, Spain
| | - Javier Martinez-Picado
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Roger Paredes
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- Universitat Autònoma de Barcelona, Barcelona, Spain
- “Lluita contra la SIDA” Foundation, Hospital Germans Trias i Pujol, Badalona, Spain
- University of VIC and Central Catalonia, Vic, Spain
| | - Christian Brander
- IrsiCaixa AIDS Research Institute—HIVACAT, Hospital Germans Trias i Pujol, Badalona, Spain
- University of VIC and Central Catalonia, Vic, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| |
Collapse
|
|
39
|
Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection. AIDS 2017. [PMID: 28650381 DOI: 10.1097/qad.0000000000001575] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. METHODS We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in-vitro replication as a surrogate of mutation stability following transmission. RESULTS Reverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. sub-Saharan Africa, Southeastern Europe) where B18 is more common. This, along with the observation that reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. CONCLUSIONS Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP.
Collapse
|
|
40
|
Gorin AM, Du Y, Liu FY, Zhang TH, Ng HL, Hofmann C, Cumberland WG, Sun R, Yang OO. HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes. PLoS Pathog 2017; 13:e1006541. [PMID: 28787455 PMCID: PMC5560751 DOI: 10.1371/journal.ppat.1006541] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 08/17/2017] [Accepted: 07/19/2017] [Indexed: 01/11/2023] Open
Abstract
Certain Major Histocompatibility-I (MHC-I) types are associated with superior immune containment of HIV-1 infection by CD8+ cytotoxic T lymphocytes (CTLs), but the mechanisms mediating this containment are difficult to elucidate in vivo. Here we provide controlled assessments of fitness landscapes and CTL-imposed constraints for immunodominant epitopes presented by two protective (B*57 and B*27) and one non-protective (A*02) MHC-I types. Libraries of HIV-1 with saturation mutagenesis of CTL epitopes are propagated with and without CTL selective pressure to define the fitness landscapes for epitope mutation and escape from CTLs via deep sequencing. Immunodominant B*57- and B*27- present epitopes are highly limited in options for fit mutations, with most viable variants recognizable by CTLs, whereas an immunodominant A*02 epitope-presented is highly permissive for mutation, with many options for CTL evasion without loss of viability. Generally, options for evasion overlap considerably between CTL clones despite highly distinct T cell receptors. Finally, patterns of variant recognition suggest population-wide CTL selection for the A*02-presented epitope. Overall, these findings indicate that these protective MHC-I types yield CTL targeting of highly constrained epitopes, and underscore the importance of blocking public escape pathways for CTL-based interventions against HIV-1. Certain MHC class I types are associated with superior immune containment of HIV-1, underscoring the importance of CD8+ cytotoxic T lymphocytes (CTLs). Epitope escape mutations for these types is limited, indicating reduced immune evasion. Two proposed mechanisms are: 1) CTL targeting of highly sequence-constrained epitopes, or 2) more promiscuous CTLs for epitope variation. However, the in vivo complexity of undefined starting virus, multiple targeted epitopes, polyclonal CTL responses against each epitope, and post-hoc evaluation of the interaction renders examination of mechanisms difficult. Here we approach this question with controlled prospective in vitro experiments using saturation mutagenesis of epitopes in clonal HIV-1, propagated in the absence or presence of CTL clones to define the options for epitope mutation and immune evasion by deep sequencing. We find that two immunodominant epitopes presented by protective MHC types are highly mutation-constrained compared to one presented by a non-protective MHC type, whereas CTL promiscuity for epitope variation is not appreciably different. These results suggest that these protective MHC types are associated with limited HIV-1 escape predominately due to intrinsic constraints on epitope mutation, and underscore the importance of focusing the CTL response on highly conserved epitopes for immunotherapies and vaccines.
Collapse
Affiliation(s)
- Aleksandr M. Gorin
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Yushen Du
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Franklin Y. Liu
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Tian-Hao Zhang
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America
| | - Hwee L. Ng
- Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - Christian Hofmann
- Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
| | - William G. Cumberland
- Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, California, United States of America
| | - Ren Sun
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America
| | - Otto O. Yang
- Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
- AIDS Healthcare Foundation, Los Angeles, California, United States of America
- * E-mail:
| |
Collapse
|
|
41
|
Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression. J Virol 2017; 91:JVI.00253-17. [PMID: 28424286 DOI: 10.1128/jvi.00253-17] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/30/2017] [Indexed: 11/20/2022] Open
Abstract
There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates (r = 0.51; P = 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-protease-driven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases (P < 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C < D < intersubtype recombinants (P < 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gag-protease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes.IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with the replication capacity of whole virus isolates. We further show that subtype B displays a significantly higher Gag-protease-mediated replication capacity than does subtype C, and we identify a major genetic determinant of these differences. Moreover, in two independent East African cohorts we demonstrate a reproducible hierarchy of Gag-protease-driven replicative capacity, whereby recombinants exhibit the greatest replication, followed by subtype D, followed by subtypes A and C. Our data identify Gag-protease as a major determinant of subtype differences in disease progression among HIV-1 subtypes; furthermore, we propose that the poorer viral replicative capacity of subtypes A and C may paradoxically contribute to their more efficient spread in sub-Saharan Africa.
Collapse
|
|
42
|
Chakraborty AK, Barton JP. Rational design of vaccine targets and strategies for HIV: a crossroad of statistical physics, biology, and medicine. REPORTS ON PROGRESS IN PHYSICS. PHYSICAL SOCIETY (GREAT BRITAIN) 2017; 80:032601. [PMID: 28059778 DOI: 10.1088/1361-6633/aa574a] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Vaccination has saved more lives than any other medical procedure. Pathogens have now evolved that have not succumbed to vaccination using the empirical paradigms pioneered by Pasteur and Jenner. Vaccine design strategies that are based on a mechanistic understanding of the pertinent immunology and virology are required to confront and eliminate these scourges. In this perspective, we describe just a few examples of work aimed to achieve this goal by bringing together approaches from statistical physics with biology and clinical research.
Collapse
Affiliation(s)
- Arup K Chakraborty
- Departments of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Departments of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Departments of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Departments of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, United States of America. Ragon Institute of MIT, MGH, & Harvard, Cambridge, MA 02139, United States of America
| | | |
Collapse
|
|
43
|
Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome. PLoS One 2017; 12:e0172206. [PMID: 28212411 PMCID: PMC5315389 DOI: 10.1371/journal.pone.0172206] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/23/2017] [Indexed: 01/05/2023] Open
Abstract
T97A is an HIV-1 integrase polymorphism associated with integrase strand transfer inhibitor (INSTI) resistance. Using pooled data from 16 clinical studies, we investigated the prevalence of T97A (pre-existing and emergent) and its impact on INSTI susceptibility and treatment response in INSTI-naive patients who enrolled on elvitegravir (EVG)- or raltegravir (RAL)-based regimens. Prior to INSTI-based therapy, primary INSTI resistance-associated mutations (RAMs) were absent and T97A pre-existed infrequently (1.4%; 47 of 3367 integrase sequences); most often among non-B (5.3%) than B (0.9%) HIV-1 subtypes. During INSTI-based therapy, few patients experienced virologic failure with emergent INSTI RAMs (3%; 122 of 3881 patients), among whom T97A emerged infrequently in the presence (n = 6) or absence (n = 8) of primary INSTI RAMs. A comparison between pre-existing and emergent T97A patient populations (i.e., in the absence of primary INSTI RAMs) showed no significant differences in EVG or RAL susceptibility in vitro. Furthermore, among all T97A-containing viruses tested, only 38-44% exhibited reduced susceptibility to EVG and/or RAL (all of low magnitude; <11-fold), while all maintained susceptibility to dolutegravir. Of the patients with pre-existing T97A, 17 had available clinical follow-up: 16 achieved virologic suppression and 1 maintained T97A and INSTI sensitivity without further resistance development. Overall, T97A is an infrequent integrase polymorphism that is enriched among non-B HIV-1 subtypes and can confer low-level reduced susceptibility to EVG and/or RAL. However, detection of T97A does not affect response to INSTI-based therapy with EVG or RAL. These results suggest a very low risk of initiating INSTI-based therapy in patients with pre-existing T97A.
Collapse
|
|
44
|
Accumulation of Pol Mutations Selected by HLA-B*52:01-C*12:02 Protective Haplotype-Restricted Cytotoxic T Lymphocytes Causes Low Plasma Viral Load Due to Low Viral Fitness of Mutant Viruses. J Virol 2017; 91:JVI.02082-16. [PMID: 27903797 DOI: 10.1128/jvi.02082-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 11/21/2016] [Indexed: 01/22/2023] Open
Abstract
HLA-B*52:01-C*12:02, which is the most abundant haplotype in Japan, has a protective effect on disease progression in HIV-1-infected Japanese individuals, whereas HLA-B*57 and -B*27 protective alleles are very rare in Japan. A previous study on HLA-associated polymorphisms demonstrated that the number of HLA-B*52:01-associated mutations at four Pol positions was inversely correlated with plasma viral load (pVL) in HLA-B*52:01-negative individuals, suggesting that the transmission of HIV-1 with these mutations could modulate the pVL in the population. However, it remains unknown whether these mutations were selected by HLA-B*52:01-restricted CTLs and also reduced viral fitness. In this study, we identified two HLA-B*52:01-restricted and one HLA-C*12:02-restricted novel cytotoxic T-lymphocyte (CTL) epitopes in Pol. Analysis using CTLs specific for these three epitopes demonstrated that these CTLs failed to recognize mutant epitopes or more weakly recognized cells infected with mutant viruses than wild-type virus, supporting the idea that these mutations were selected by the HLA-B*52:01- or HLA-C*12:02-restricted T cells. We further showed that these mutations reduced viral fitness, although the effect of each mutation was weak. The present study demonstrated that the accumulation of these Pol mutations selected by HLA-B*52:01- or HLA-C*12:02-restricted CTLs impaired viral replication capacity and thus reduced the pVL. The fitness cost imposed by the mutations partially accounted for the effect of the HLA-B*52:01-C*12:02 haplotype on clinical outcome, together with the effect of HLA-B*52:01-restricted CTLs on viral replication, which had been previously demonstrated. IMPORTANCE Numerous population-based studies identified HLA-associated HIV-1 mutations to predict HIV-1 escape mutations from cytotoxic T lymphocytes (CTLs). However, the majority of these HLA-associated mutations have not been identified as CTL escape mutations. Our previous population-based study showed that five HLA-B*52:01-associated mutations at four Pol positions were inversely correlated with the plasma viral load in HLA-B*52:01-negative Japanese individuals. In the present study, we demonstrated that these mutations were indeed selected by CTLs specific for novel B*52:01- and C*12:02-restricted epitopes and that the accumulation of these mutations reduced the viral fitness in vitro This study elucidated the mechanism by which the accumulation of these CTL escape mutations contributed to the protective effect of the HLA-B*52:01-HLA-C*12:02 haplotype on disease progression in HIV-1-infected Japanese individuals.
Collapse
|
|
45
|
Kamori D, Ueno T. HIV-1 Tat and Viral Latency: What We Can Learn from Naturally Occurring Sequence Variations. Front Microbiol 2017; 8:80. [PMID: 28194140 PMCID: PMC5276809 DOI: 10.3389/fmicb.2017.00080] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Accepted: 01/11/2017] [Indexed: 01/25/2023] Open
Abstract
Despite the effective use of antiretroviral therapy, the remainder of a latently HIV-1-infected reservoir mainly in the resting memory CD4+ T lymphocyte subset has provided a great setback toward viral eradication. While host transcriptional silencing machinery is thought to play a dominant role in HIV-1 latency, HIV-1 protein such as Tat, may affect both the establishment and the reversal of latency. Indeed, mutational studies have demonstrated that insufficient Tat transactivation activity can result in impaired transcription of viral genes and the establishment of latency in cell culture experiments. Because Tat protein is one of highly variable proteins within HIV-1 proteome, it is conceivable that naturally occurring Tat mutations may differentially modulate Tat functions, thereby influencing the establishment and/or the reversal of viral latency in vivo. In this mini review, we summarize the recent findings of Tat naturally occurring polymorphisms associating with host immune responses and we highlight the implication of Tat sequence variations in relation to HIV latency.
Collapse
Affiliation(s)
- Doreen Kamori
- Center for AIDS Research, Kumamoto University Kumamoto, Japan
| | - Takamasa Ueno
- Center for AIDS Research, Kumamoto UniversityKumamoto, Japan; International Research Center for Medical Sciences, Kumamoto UniversityKumamoto, Japan
| |
Collapse
|
|
46
|
Early evolution of human leucocyte antigen-associated escape mutations in variable Gag proteins predicts CD4+ decline in HIV-1 subtype C-infected women. AIDS 2017; 31:191-197. [PMID: 27755110 DOI: 10.1097/qad.0000000000001298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE HIV-1 escape from cytotoxic T-lymphocytes results in the accumulation of human leucocyte antigen (HLA)-associated mutations in the viral genome. To understand the contribution of early escape to disease progression, this study investigated the evolution and pathogenic implications of cytotoxic T-lymphocyte escape in a cohort followed from infection for 5 years. METHODS Viral loads and CD4 cell counts were monitored in 78 subtype C-infected individuals from onset of infection until CD4 cell count decline to less than 350 cells/μl or 5 years postinfection. The gag gene was sequenced and HLA-associated changes between enrolment and 12 months postinfection were mapped. RESULTS HLA-associated escape mutations were identified in 48 (62%) of the participants and were associated with CD4 decline to less than 350 cells/μl (P = 0.05). Escape mutations in variable Gag proteins (p17 and p7p6) had a greater impact on disease progression than escape in more conserved regions (p24) (P = 0.03). The association between HLA-associated escape mutations and CD4 decline was independent of protective HLA allele (B57, B58 : 01 and B81) expression. CONCLUSION The high frequency of escape contributed to rapid disease progression in this cohort. Although HLA-adaption in both conserved and variable Gag domains in the first year of infection was detrimental to long-term clinical outcome, escape in variable domains had greater impact.
Collapse
|
|
47
|
Wagner TA. Combining Cell and Gene Therapy in an Effort to Eradicate HIV. AIDS Patient Care STDS 2016; 30:534-538. [PMID: 27905840 DOI: 10.1089/apc.2016.0226] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
More than 30 million people are infected with HIV, and HIV remains the fifth leading cause of disability-adjusted life years worldwide. Antiretroviral therapy (ART) dramatically decreases mortality rate, but there are side effects, long-term toxicities, expenses, stigmas, and inconveniences associated with chronic treatment, and HIV-infected individuals on ART have an increased risk of malignancies, cardiovascular disease, neurologic disease, and shortened life expectancy. Therefore, a cure for HIV remains an important goal. Combining new cell and gene therapy technology is an exciting approach that appears promising in vitro. Animal testing and careful clinical trials will be needed to determine if these strategies are clinically useful.
Collapse
Affiliation(s)
- Thor A. Wagner
- Department of Pediatrics, University of Washington, Seattle, Washington
- Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington
| |
Collapse
|
|
48
|
Mónaco DC, Dilernia DA, Fiore-Gartland A, Yu T, Prince JL, Dennis KK, Qin K, Schaefer M, Claiborne DT, Kilembe W, Tang J, Price MA, Farmer P, Gilmour J, Bansal A, Allen S, Goepfert P, Hunter E. Balance between transmitted HLA preadapted and nonassociated polymorphisms is a major determinant of HIV-1 disease progression. J Exp Med 2016; 213:2049-63. [PMID: 27551154 PMCID: PMC5030801 DOI: 10.1084/jem.20151984] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 07/25/2016] [Indexed: 11/05/2022] Open
Abstract
In a cohort of Zambian heterosexual transmission pairs, the authors show that HIV-1–transmitted variants already exhibit a significant degree of preadaptation to the new host's HLA alleles, which, modulated by polymorphisms that decrease viral fitness, determines early set-point VL and the rate of disease progression in the newly infected individual. HIV-1 adapts to a new host through mutations that facilitate immune escape. Here, we evaluate the impact on viral control and disease progression of transmitted polymorphisms that were either preadapted to or nonassociated with the new host’s HLA. In a cohort of 169 Zambian heterosexual transmission pairs, we found that almost one-third of possible HLA-linked target sites in the transmitted virus Gag protein are already adapted, and that this transmitted preadaptation significantly reduced early immune recognition of epitopes. Transmitted preadapted and nonassociated polymorphisms showed opposing effects on set-point VL and the balance between the two was significantly associated with higher set-point VLs in a multivariable model including other risk factors. Transmitted preadaptation was also significantly associated with faster CD4 decline (<350 cells/µl) and this association was stronger after accounting for nonassociated polymorphisms, which were linked with slower CD4 decline. Overall, the relative ratio of the two classes of polymorphisms was found to be the major determinant of CD4 decline in a multivariable model including other risk factors. This study reveals that, even before an immune response is mounted in the new host, the balance of these opposing factors can significantly influence the outcome of HIV-1 infection.
Collapse
Affiliation(s)
| | | | - Andrew Fiore-Gartland
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
| | - Tianwei Yu
- Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322
| | | | | | - Kai Qin
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233
| | | | | | | | - Jianming Tang
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233
| | - Matt A Price
- International AIDS Vaccine Initiative (IAVI), San Francisco, CA 94105 Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94105
| | - Paul Farmer
- Emory Vaccine Center, Emory University, Atlanta, GA 30322
| | | | - Anju Bansal
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233
| | - Susan Allen
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322
| | - Paul Goepfert
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233
| | - Eric Hunter
- Emory Vaccine Center, Emory University, Atlanta, GA 30322 Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322
| |
Collapse
|
|
49
|
Kamori D, Hasan Z, Ohashi J, Kawana-Tachikawa A, Gatanaga H, Oka S, Ueno T. Identification of two unique naturally occurring Vpr sequence polymorphisms associated with clinical parameters in HIV-1 chronic infection. J Med Virol 2016; 89:123-129. [PMID: 27328918 DOI: 10.1002/jmv.24612] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2016] [Indexed: 01/08/2023]
Abstract
HIV-1 viral protein R (Vpr) plays important roles in HIV-1 replication. Despite the identification of a number of HLA class I-associated immune escape mutations; it is yet known whether immune-driven Vpr polymorphisms are associated with disease outcome. Hereby, we comprehensively analyzed Vpr sequence polymorphisms and their association with disease outcome and host HLA genotypes, by using plasma viral RNA isolated from 444 HLA-typed, treatment-naïve, chronically HIV-1 infected individuals. Vpr amino acid residues at positions 13, 37, 45, 55, 63, 77, 84, 85, 86, and 93 were significantly associated with patients' plasma viral load and/or CD4 count. Further analysis revealed Ala at position 55 was significantly associated with lower plasma viral load; and Thr at position 63 was significantly associated with lower plasma viral load and higher CD4 count. Also, the number of amino acid residues at the two positions, located in a functionally important α-helical domain, correlated inversely with plasma viral load and positively with CD4 count. Moreover, a phylogenetically corrected method revealed residues at positions 55 and 63 are associated with patients' HLA genotypes. Taken together, our results suggest that Vpr polymorphisms at functionally important and immune-reactive sites may contribute, at least in part, to viral replication and disease outcome in vivo. J. Med. Virol. 89:123-129, 2017. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Doreen Kamori
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Zafrul Hasan
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Jun Ohashi
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan
| | - Ai Kawana-Tachikawa
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan.,Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Gatanaga
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan.,AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shinichi Oka
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan.,AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Takamasa Ueno
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan. .,International Research Center for Medical Sciences (IRCMS), Kumamoto University, Kumamoto, Japan.
| |
Collapse
|
|
50
|
Sun X, Shi Y, Akahoshi T, Fujiwara M, Gatanaga H, Schönbach C, Kuse N, Appay V, Gao GF, Oka S, Takiguchi M. Effects of a Single Escape Mutation on T Cell and HIV-1 Co-adaptation. Cell Rep 2016; 15:2279-2291. [PMID: 27239036 DOI: 10.1016/j.celrep.2016.05.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 04/13/2016] [Accepted: 05/02/2016] [Indexed: 12/31/2022] Open
Abstract
The mechanistic basis for the progressive accumulation of Y(135)F Nef mutant viruses in the HIV-1-infected population remains poorly understood. Y(135)F viruses carry the 2F mutation within RW8 and RF10, which are two HLA-A(∗)24:02-restricted superimposed Nef epitopes recognized by distinct and adaptable CD8(+) T cell responses. We combined comprehensive analysis of the T cell receptor repertoire and cross-reactive potential of wild-type or 2F RW8- and RF10-specific CD8(+) T cells with peptide-MHC complex stability and crystal structure studies. We find that, by affecting direct and water-mediated hydrogen bond networks within the peptide-MHC complex, the 2F mutation reduces both TCR and HLA binding. This suggests an advantage underlying the evolution of the 2F variant with decreased CD8(+) T cell efficacy. Our study provides a refined understanding of HIV-1 and CD8(+) T cell co-adaptation at the population level.
Collapse
Affiliation(s)
- Xiaoming Sun
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Yi Shi
- Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Tomohiro Akahoshi
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Mamoru Fujiwara
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Hiroyuki Gatanaga
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Christian Schönbach
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; Department of Biology, School of Science and Technology, Nazarbayev University, Astana 010000, Republic of Kazakhstan
| | - Nozomi Kuse
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan
| | - Victor Appay
- International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; INSERM, Unité Mixte de Recherche 1135, Sorbonne Universités, Université Pierre et Marie Curie, Université Paris 06, Centre d'Immunologie et des Maladies Infectieuses-Paris, 75013 Paris, France
| | - George F Gao
- Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Shinichi Oka
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo 162-8655, Japan
| | - Masafumi Takiguchi
- Center for AIDS Research, Kumamoto University, Kumamoto 860-0811, Japan; International Research Center of Medical Sciences (IRCMS), Kumamoto University, Kumamoto 860-0811, Japan; Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
| |
Collapse
|