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Tioka L, Diez RC, Sönnerborg A, van de Klundert MAA. Latency Reversing Agents and the Road to an HIV Cure. Pathogens 2025; 14:232. [PMID: 40137717 PMCID: PMC11944434 DOI: 10.3390/pathogens14030232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/12/2025] [Accepted: 02/18/2025] [Indexed: 03/29/2025] Open
Abstract
HIV-1 infection cannot be cured due to the presence of HIV-1 latently infected cells. These cells do not produce the virus, but they can resume virus production at any time in the absence of antiretroviral therapy. Therefore, people living with HIV (PLWH) need to take lifelong therapy. Strategies have been coined to eradicate the viral reservoir by reactivating HIV-1 latently infected cells and subsequently killing them. Various latency reversing agents (LRAs) that can reactivate HIV-1 in vitro and ex vivo have been identified. The most potent LRAs also strongly activate T cells and therefore cannot be applied in vivo. Many LRAs that reactivate HIV in the absence of general T cell activation have been identified and have been tested in clinical trials. Although some LRAs could reduce the reservoir size in clinical trials, so far, they have failed to eradicate the reservoir. More recently, immune modulators have been applied in PLWH, and the first results seem to indicate that these may reduce the reservoir and possibly improve immunological control after therapy interruption. Potentially, combinations of LRAs and immune modulators could reduce the reservoir size, and in the future, immunological control may enable PLWH to live without developing HIV-related disease in the absence of therapy.
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Affiliation(s)
- Louis Tioka
- Faculty of Medicine, Erlangen-Nürnberg, Friedrich-Alexander-Universität, 91054 Erlangen, Germany;
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
| | - Rafael Ceña Diez
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
| | - Anders Sönnerborg
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
- Department of Infectious Diseases, Karolinska University Hospital, 17177 Stockholm, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Maarten A. A. van de Klundert
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
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2
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King HAD, Pokkali S, Kim D, Brammer D, Song K, McCarthy E, Lehman C, Todd JP, Foulds KE, Darrah PA, Seder RA, Bolton DL, Roederer M. Immune Activation Profiles Elicited by Distinct, Repeated TLR Agonist Infusions in Rhesus Macaques. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1643-1655. [PMID: 37861342 PMCID: PMC10656433 DOI: 10.4049/jimmunol.2300424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/28/2023] [Indexed: 10/21/2023]
Abstract
TLR agonists are a promising class of immune system stimulants investigated for immunomodulatory applications in cancer immunotherapy and viral diseases. In this study, we sought to characterize the safety and immune activation achieved by different TLR agonists in rhesus macaques (Macaca mulatta), a useful preclinical model of complex immune interactions. Macaques received one of three TLR agonists, followed by plasma cytokine, immune cell subset representation, and blood cell activation measurements. The TLR4 agonist LPS administered i.v. induced very transient immune activation, including TNF-α expression and monocyte activation. The TLR7/8 agonist 2BXy elicited more persistent cytokine expression, including type I IFN, IL-1RA, and the proinflammatory IL-6, along with T cell and monocyte activation. Delivery of 2BXy i.v. and i.m. achieved comparable immune activation, which increased with escalating dose. Finally, i.v. bacillus Calmette-Guérin (BCG) vaccination (which activates multiple TLRs, especially TLR2/4) elicited the most pronounced and persistent innate and adaptive immune response, including strong induction of IFN-γ, IL-6, and IL-1RA. Strikingly, monocyte, T cell, and NK cell expression of the proliferation marker Ki67 increased dramatically following BCG vaccination. This aligned with a large increase in total and BCG-specific cells measured in the lung. Principal component analysis of the combined cytokine expression and cellular activation responses separated animals by treatment group, indicating distinct immune activation profiles induced by each agent. In sum, we report safe, effective doses and routes of administration for three TLR agonists that exhibit discrete immunomodulatory properties in primates and may be leveraged in future immunotherapeutic strategies.
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Affiliation(s)
- Hannah A. D. King
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Supriya Pokkali
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Dohoon Kim
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Daniel Brammer
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Kaimei Song
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | | | - Chelsea Lehman
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - John-Paul Todd
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Kathryn E. Foulds
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | | | - Robert A. Seder
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
| | - Diane L. Bolton
- U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD
| | - Mario Roederer
- Vaccine Research Center, National Institutes of Health, Bethesda, MD
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3
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Sachdeva M, Taneja S, Sachdeva N. Stem cell-like memory T cells: Role in viral infections and autoimmunity. World J Immunol 2023; 13:11-22. [DOI: 10.5411/wji.v13.i2.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/06/2023] [Accepted: 07/27/2023] [Indexed: 08/14/2023] Open
Abstract
Stem cell-like memory T (TSCM) cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases. Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization. In case of chronic viral diseases such as human immunodeficiency virus-1, CD4+ TSCM cells, serve as major reservoirs of the latent virus. However, during immune activation and functional exhaustion of effector T cells, these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection. More recently, these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion. Similarly, studies are also investigating their pathological role in driving autoimmune responses. However, there are several gaps in the understanding of the role of TSCM cells in viral and autoimmune diseases to make them potential therapeutic targets. In this minireview, we have attempted an updated compilation of the dyadic role of these complex TSCM cells during such human diseases along with their biology and transcriptional programs.
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Affiliation(s)
- Meenakshi Sachdeva
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Shivangi Taneja
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
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4
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Li Y, Wang Z, Hou Y, Liu X, Hong J, Shi X, Huang X, Zhang T, Liao X, Zhang L. Novel TLR7/8 agonists promote activation of HIV-1 latent reservoirs and human T and NK cells. Front Microbiol 2023; 14:1033448. [PMID: 36778871 PMCID: PMC9911797 DOI: 10.3389/fmicb.2023.1033448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/12/2023] [Indexed: 01/28/2023] Open
Abstract
Antiretroviral therapy can successfully suppress HIV-1 replication to undetectable levels but fails to eliminate latent and persistent HIV-1 reservoirs. Recent studies have focused on the immunomodulatory agents such as Toll-like receptor 7 and 8 (TLR7 and TLR8) capable of activating, thereby rendering the reservoir susceptible to antiretroviral inhibition and immune recognition and elimination. In this context, this study focused on generating a diverse repertoire of TLR7/8 agonists to identify more potent candidates for activating latent HIV-1 and immune cells' response. Through combinational strategies of computer-aided design and biological characterization, 159 pyrido [3,2-d] pyrimidine and pyridine-2-amine-based derivatives were synthesized. Of which, two TLR7/8 dual and one TLR8-specific agonists with exceptionally high potency in activating HIV-1 latent reservoirs in cell lines and PBMCs of patients with persistent and durable virologic controls were identified. Particularly, these agonists appeared to enhance NK and T cells activity, which were correlated with the degree of surface activation markers. The outcome of this study highlights the remarkable potential of TLR7/8 agonists in simultaneously activating HIV-1 from the latently infected cells and augmenting immune effector cells.
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Affiliation(s)
- Yangyang Li
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China
| | - Zhisong Wang
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China
| | - Ying Hou
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China
| | - Xiaoyu Liu
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China
| | - Junxian Hong
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China
| | - Xuanling Shi
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China
| | - Xiaojie Huang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhang
- Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Xuebin Liao
- Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China,*Correspondence: Xuebin Liao, ✉
| | - Linqi Zhang
- Department of Basic Medical Sciences, School of Medicine, NexVac Research Center, Comprehensive AIDS Research Center, Tsinghua University, Beijing, China,Linqi Zhang, ✉
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5
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Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation. MOLECULES (BASEL, SWITZERLAND) 2022; 28:molecules28010003. [PMID: 36615199 PMCID: PMC9822059 DOI: 10.3390/molecules28010003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/12/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called 'shock-and-kill' regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection.
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6
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Inderbitzin A, Loosli T, Opitz L, Rusert P, Metzner KJ. Transcriptome profiles of latently- and reactivated HIV-1 infected primary CD4+ T cells: A pooled data-analysis. Front Immunol 2022; 13:915805. [PMID: 36090997 PMCID: PMC9459035 DOI: 10.3389/fimmu.2022.915805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
The main obstacle to cure HIV-1 is the latent reservoir. Antiretroviral therapy effectively controls viral replication, however, it does not eradicate the latent reservoir. Latent CD4+ T cells are extremely rare in HIV-1 infected patients, making primary CD4+ T cell models of HIV-1 latency key to understanding latency and thus finding a cure. In recent years several primary CD4+ T cell models of HIV-1 latency were developed to study the underlying mechanism of establishing, maintaining and reversing HIV-1 latency. In the search of biomarkers, primary CD4+ T cell models of HIV-1 latency were used for bulk and single-cell transcriptomics. A wealth of information was generated from transcriptome analyses of different primary CD4+ T cell models of HIV-1 latency using latently- and reactivated HIV-1 infected primary CD4+ T cells. Here, we performed a pooled data-analysis comparing the transcriptome profiles of latently- and reactivated HIV-1 infected cells of 5 in vitro primary CD4+ T cell models of HIV-1 latency and 2 ex vivo studies of reactivated HIV-1 infected primary CD4+ T cells from HIV-1 infected individuals. Identifying genes that are differentially expressed between latently- and reactivated HIV-1 infected primary CD4+ T cells could be a more successful strategy to better understand and characterize HIV-1 latency and reactivation. We observed that natural ligands and coreceptors were predominantly downregulated in latently HIV-1 infected primary CD4+ T cells, whereas genes associated with apoptosis, cell cycle and HLA class II were upregulated in reactivated HIV-1 infected primary CD4+ T cells. In addition, we observed 5 differentially expressed genes that co-occurred in latently- and reactivated HIV-1 infected primary CD4+ T cells, one of which, MSRB2, was found to be differentially expressed between latently- and reactivated HIV-1 infected cells. Investigation of primary CD4+ T cell models of HIV-1 latency that mimic the in vivo state remains essential for the study of HIV-1 latency and thus providing the opportunity to compare the transcriptome profile of latently- and reactivated HIV-1 infected cells to gain insights into differentially expressed genes, which might contribute to HIV-1 latency.
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Affiliation(s)
- Anne Inderbitzin
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
- Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland
| | - Tom Loosli
- Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland
- Institute of Medical Virology, University of Zurich, Zurich, Switzerland
- Life Science Zurich Graduate School, University of Zurich, Zurich, Switzerland
| | - Lennart Opitz
- Functional Genomics Center Zurich, Eidgenössische Technische Hochschule (ETH) Zürich/University of Zurich, Zurich, Switzerland
| | - Peter Rusert
- Institute of Medical Virology, University of Zurich, Zurich, 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
- *Correspondence: Karin J. Metzner,
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7
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Chen J, Zhou T, Zhang Y, Luo S, Chen H, Chen D, Li C, Li W. The reservoir of latent HIV. Front Cell Infect Microbiol 2022; 12:945956. [PMID: 35967854 PMCID: PMC9368196 DOI: 10.3389/fcimb.2022.945956] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
The persistence of latent reservoir of the human immunodeficiency virus (HIV) is currently the major challenge in curing HIV infection. After HIV infects the human body, the latent HIV is unable to be recognized by the body’s immune system. Currently, the widely adopted antiretroviral therapy (ART) is also unble to eliminate it, thus hindering the progress of HIV treatment. This review discusses the existence of latent HIV vault for HIV treatment, its formation and factors affecting its formation, cell, and tissue localization, methods for detection and removing latent reservoir, to provide a comprehensive understanding of latent HIV vault, in order to assist in the future research and play a potential role in achieving HIV treatment.
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Affiliation(s)
- Jing Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Tong Zhou
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yuan Zhang
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Shumin Luo
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Huan Chen
- Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Chuanyun Li
- Beijing Youan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Chuanyun Li, ; Weihua Li,
| | - Weihua Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Chuanyun Li, ; Weihua Li,
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8
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Abana CZY, Lamptey H, Bonney EY, Kyei GB. HIV cure strategies: which ones are appropriate for Africa? Cell Mol Life Sci 2022; 79:400. [PMID: 35794316 PMCID: PMC9259540 DOI: 10.1007/s00018-022-04421-z] [Citation(s) in RCA: 6] [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: 02/24/2022] [Revised: 06/09/2022] [Accepted: 06/10/2022] [Indexed: 11/10/2022]
Abstract
Although combination antiretroviral therapy (ART) has reduced mortality and improved lifespan for people living with HIV, it does not provide a cure. Patients must be on ART for the rest of their lives and contend with side effects, unsustainable costs, and the development of drug resistance. A cure for HIV is, therefore, warranted to avoid the limitations of the current therapy and restore full health. However, this cure is difficult to find due to the persistence of latently infected HIV cellular reservoirs during suppressive ART. Approaches to HIV cure being investigated include boosting the host immune system, genetic approaches to disable co-receptors and the viral genome, purging cells harboring latent HIV with latency-reversing latency agents (LRAs) (shock and kill), intensifying ART as a cure, preventing replication of latent proviruses (block and lock) and boosting T cell turnover to reduce HIV-1 reservoirs (rinse and replace). Since most people living with HIV are in Africa, methods being developed for a cure must be amenable to clinical trials and deployment on the continent. This review discusses the current approaches to HIV cure and comments on their appropriateness for Africa.
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Affiliation(s)
- Christopher Zaab-Yen Abana
- Department of Virology, College of Health Sciences, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Helena Lamptey
- Department of Immunology, College of Health Sciences, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - Evelyn Y Bonney
- Department of Virology, College of Health Sciences, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana
| | - George B Kyei
- Department of Virology, College of Health Sciences, Noguchi Memorial Institute for Medical Research, University of Ghana, Accra, Ghana.
- Departments of Medicine and Molecular Microbiology, Washington University in St. Louis, 660 S. Euclid Ave, St. Louis, MO, USA.
- Medical and Scientific Research Center, University of Ghana Medical Centre, Accra, Ghana.
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Sustainable antiviral efficacy of rejuvenated HIV-specific cytotoxic T lymphocytes generated from induced pluripotent stem cells. J Virol 2022; 96:e0221721. [DOI: 10.1128/jvi.02217-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Persistence of HIV latently infected cells is a barrier to HIV cure. The "kick and kill" strategy for cure includes clearance of the viral reservoir by HIV-specific cytotoxic T lymphocytes (CTLs). However, exhaustion and senescence of T cells accelerates during HIV infection, and does not fully recover, despite complete viral suppression under antiretroviral therapy. We previously established an induced pluripotent stem cell (iPSC) from a parental HIV-specific CTL clone and generated an iPSC-derived rejuvenated HIV-specific CTL clone (iPSC-CTL), which exhibited an early memory phenotype, high proliferation capacity and effector functions
in vitro
. Here, we assessed the antiviral efficacy of the HIV-specific iPSC-CTL by single- and multiple-round viral suppression assays (VSAs). The HIV-specific iPSC-CTL suppressed viral replication in an HLA-dependent manner with equivalent efficacy to the parental CTL clone in single-round VSA. In multiple-round VSA, however, the ability of the iPSC-CTL to suppress viral replication was longer than that of the parental CTL clone. These results indicate that HIV-specific iPSC-CTL can sustainably exert suppressive pressure on viral replication, suggesting a novel approach to facilitate clearance of the HIV reservoir via adoptive transfer of rejuvenated CTLs.
Importance
Elimination of latently HIV-infected cells is required for HIV cure. In the “kick and kill” strategy proposed for HIV cure, the host immune system, including HIV-specific cytotoxic T lymphocytes (CTLs), play a central role in eliminating HIV antigen-expressing cells following reactivation by latency-reversing agents (LRAs). However, CTL dysfunction due to exhaustion and senescence in chronic HIV infection can be an obstacle to this strategy. Adoptive transfer with effective HIV-specific CTLs may be a solution of this problem. We previously generated an induced pluripotent stem cell (iPSC)-derived rejuvenated HIV-specific CTL clone (iPSC-CTL) with high functional and proliferative capacity. The present study demonstrates that iPSC-CTL can survive and suppress HIV replication
in vitro
longer than the parental CTL clone, indicating the potential of iPSC-CTL to sustainably exert suppressive pressure on viral replication. Adoptive transfer with rejuvenated HIV-specific CTLs in combination with LRAs may be a new intervention strategy for HIV cure/remission.
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Huang X, Zhang X, Lu M. Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics. Expert Opin Drug Discov 2021; 16:869-880. [PMID: 33678093 DOI: 10.1080/17460441.2021.1898369] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Toll-like receptor (TLR) 7 and TLR8 are functionally localized to endosomes and recognize specific RNA sequences. They play crucial roles in initiating innate and adaptive immune responses. TLR7/8 activation protects the host against invading pathogens and enhances immune responses. In contrast, sustained TLR7/8 signaling leads to immune overreaction. Therefore, agonists or antagonists targeting TLR7/8 signaling are favorable drug candidates for the treatment of immune disorders.Areas covered: Basic knowledge about TLR7 and TLR8 and their signaling pathways are briefly reviewed. Various therapeutic agents have been designed to activate or antagonize TLR7/8 signaling pathways, and their safety and efficacy for the treatment of multiple diseases have been investigated in preclinical animal models and clinical trials. TLR7/8 agonists exhibit potent antiviral activity and regulate anti-tumor immune responses. TLR7 agonists have also been used as adjuvants to improve vaccine immunogenicity and generate greater seroprotection. TLR7/8 antagonists are promising candidates for the treatment of autoimmune and inflammatory diseases.Expert opinion: TLR7/8 pathways are favorable targets for immunological therapies. Future research should concentrate on the optimization of drug safety, efficiency, and specificity. Detailed mechanistic studies will contribute to the development of TLR7/8 immunomodulators and novel therapeutic strategies.
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Affiliation(s)
- Xuan Huang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyong Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, Essen, Germany
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11
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Maina EK, Adan AA, Mureithi H, Muriuki J, Lwembe RM. A Review of Current Strategies Towards the Elimination of Latent HIV-1 and Subsequent HIV-1 Cure. Curr HIV Res 2021; 19:14-26. [PMID: 32819259 PMCID: PMC8573729 DOI: 10.2174/1570162x18999200819172009] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/02/2020] [Accepted: 07/17/2020] [Indexed: 11/30/2022]
Abstract
Background During the past 35 years, highly effective ART has saved the lives of millions of people worldwide by suppressing viruses to undetectable levels. However, this does not translate to the absence of viruses in the body as HIV persists in latent reservoirs. Indeed, rebounded HIV has been recently observed in the Mississippi and California infants previously thought to have been cured. Hence, much remains to be learned about HIV latency, and the search for the best strategy to eliminate the reservoir is the direction current research is taking. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and is applicable in human therapy is prudent for HIV eradication to be more feasible. Objectives The main barriers preventing the cure of HIV with antiretroviral therapy have been identified, progress has been made in the understanding of the therapeutic targets to which potentially eradicating drugs could be directed, integrative strategies have been proposed, and clinical trials with various alternatives are underway. The aim of this review is to provide an update on the main advances in HIV eradication, with particular emphasis on the obstacles and the different strategies proposed. The core challenges of each strategy are highlighted and the most promising strategy and new research avenues in HIV eradication strategies are proposed. Methods A systematic literature search of all English-language articles published between 2015 and 2019, was conducted using MEDLINE (PubMed) and Google scholar. Where available, medical subject headings (MeSH) were used as search terms and included: HIV, HIV latency, HIV reservoir, latency reactivation, and HIV cure. Additional search terms consisted of suppression, persistence, establishment, generation, and formation. A total of 250 articles were found using the above search terms. Out of these, 89 relevant articles related to HIV-1 latency establishment and eradication strategies were collected and reviewed, with no limitation of study design. Additional studies (commonly referenced and/or older and more recent articles of significance) were selected from bibliographies and references listed in the primary resources. Results In general, when exploring the literature, there are four main strategies heavily researched that provide promising strategies to the elimination of latent HIV: Haematopoietic Stem-Cell Transplantation, Shock and Kill Strategy, Gene-specific transcriptional activation using RNA-guided CRISPR-Cas9 system, and Block and Lock strategy. Most of the studies of these strategies are applicable in vitro, leaving many questions about the extent to which, or if any, these strategies are applicable to complex picture In vivo. However, the success of these strategies at least shows, in part, that HIV-1 can be cured, though some strategies are too invasive and expensive to become a standard of care for all HIV-infected patients. Conclusion Recent advances hold promise for the ultimate cure of HIV infection. A systems-level approach that fully recapitulates the dynamics and complexity of HIV-1 latency In vivo and applicable in human therapy is prudent for HIV eradication to be more feasible. Future studies aimed at achieving a prolonged HIV remission state are more likely to be successful if they focus on a combination strategy, including the block and kill, and stem cell approaches. These strategies propose a functional cure with minimal toxicity for patients. It is believed that the cure of HIV infection will be attained in the short term if a strategy based on purging the reservoirs is complemented with an aggressive HAART strategy.
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Affiliation(s)
- Edward K Maina
- Centre for Microbiology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya
| | - Asma A Adan
- Centre for Microbiology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya
| | - Haddison Mureithi
- Centre for Microbiology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya
| | - Joseph Muriuki
- Centre for Virology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya
| | - Raphael M Lwembe
- Centre for Virology Research-Kenya medical Research Institute, P.O Box 54840-00200, Nairobi, Kenya
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12
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HIV latency reversal agents: A potential path for functional cure? Eur J Med Chem 2021; 213:113213. [PMID: 33540228 DOI: 10.1016/j.ejmech.2021.113213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/16/2020] [Accepted: 01/12/2021] [Indexed: 12/28/2022]
Abstract
Despite the advances in Human Immunodeficiency Virus (HIV) treatment, the cure for all HIV patients still poses a major challenge, which needs to be surpassed in the coming years. Among the strategies pursuing this aim, the 'kick-and-kill' approach, which involves the reactivation and elimination of a latent HIV reservoir that resides in some CD4+ T cells, appears promising. The first step of this approach requires the use of latency reversal agents (LRAs) that induce the reactivation of the latent virus. Although several classes of LRAs have been reported so far, some limitations of these compounds still need to be overcome before their clinical use. The complete exhaustion of the reservoir of latent virus will contribute to promote the second step of this approach, facilitating the elimination of the reactivated HIV. Therefore, potent, safe, and non-toxic LRAs are necessary to promote efficient elimination of the HIV-1 virus from its reservoir. In this review article, we focus on the promising LRAs that have been described in the literature over the past few years, highlighting the advantages and disadvantages of their use in the 'kick and kill' approach, thus opening a new avenue in the development of a potential cure.
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13
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Sperber HS, Togarrati PP, Raymond KA, Bouzidi MS, Gilfanova R, Gutierrez AG, Muench MO, Pillai SK. μ-Lat: A mouse model to evaluate human immunodeficiency virus eradication strategies. FASEB J 2020; 34:14615-14630. [PMID: 32901981 PMCID: PMC8787083 DOI: 10.1096/fj.202001612rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/14/2020] [Accepted: 08/17/2020] [Indexed: 01/08/2023]
Abstract
A critical barrier to the development of a human immunodeficiency virus (HIV) cure is the lack of a scalable animal model that enables robust evaluation of eradication approaches prior to testing in humans. We established a humanized mouse model of latent HIV infection by transplanting "J-Lat" cells, Jurkat cells harboring a latent HIV provirus encoding an enhanced green fluorescent protein (GFP) reporter, into irradiated adult NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ (NSG) mice. J-Lat cells exhibited successful engraftment in several tissues including spleen, bone barrow, peripheral blood, and lung, in line with the diverse natural tissue tropism of HIV. Administration of tumor necrosis factor (TNF)-α, an established HIV latency reversal agent, significantly induced GFP expression in engrafted cells across tissues, reflecting viral reactivation. These data suggest that our murine latency ("μ-Lat") model enables efficient determination of how effectively viral eradication agents, including latency reversal agents, penetrate, and function in diverse anatomical sites harboring HIV in vivo.
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Affiliation(s)
- Hannah S. Sperber
- Vitalant Research Institute, San Francisco, California, United States of America
- Free University of Berlin, Institute of Biochemistry, Berlin, Germany
- University of California, San Francisco, California, United States of America
| | | | - Kyle A. Raymond
- Vitalant Research Institute, San Francisco, California, United States of America
- University of California, San Francisco, California, United States of America
| | - Mohamed S. Bouzidi
- Vitalant Research Institute, San Francisco, California, United States of America
- University of California, San Francisco, California, United States of America
| | - Renata Gilfanova
- Vitalant Research Institute, San Francisco, California, United States of America
| | - Alan G. Gutierrez
- Vitalant Research Institute, San Francisco, California, United States of America
| | - Marcus O. Muench
- Vitalant Research Institute, San Francisco, California, United States of America
- University of California, San Francisco, California, United States of America
| | - Satish K. Pillai
- Vitalant Research Institute, San Francisco, California, United States of America
- University of California, San Francisco, California, United States of America
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14
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Ahlenstiel CL, Symonds G, Kent SJ, Kelleher AD. Block and Lock HIV Cure Strategies to Control the Latent Reservoir. Front Cell Infect Microbiol 2020; 10:424. [PMID: 32923412 PMCID: PMC7457024 DOI: 10.3389/fcimb.2020.00424] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 07/10/2020] [Indexed: 12/14/2022] Open
Abstract
The HIV latent reservoir represents the major challenge to cure development. Residing in resting CD4+ T cells and myeloid cells at multiple locations in the body, including sanctuary sites such as the brain, the latent reservoir is not eliminated by ART and has the ability to reactivate virus replication to pre-therapy levels when ART is ceased. There are four broad areas of HIV cure research. The only successful cure strategy, thus far, is stem cell transplantation using naturally HIV resistant CCR5Δ32 stem cells. A second potential cure approach uses gene editing technology, such as zinc-finger nucleases and CRISPR/Cas9. Another two cure strategies aim to control the HIV reservoir, with polar opposite concepts; The "shock and kill" approach, which aims to "shock" or reactivate the latent virus and then "kill" infected cells via targeted immune responses. Lastly, the "block and lock" approach, which aims to enhance the latent virus state by "blocking" HIV transcription and "locking" the HIV promoter in a deep latent state via epigenetic modifications. "Shock and kill" approaches are a major focus of cure studies, however we predict that the increased specificity of "block and lock" approaches will be required for the successful development of a sustained HIV clinical remission in the absence of ART. This review focuses on the current research of novel "block and lock" approaches being explored to generate an HIV cure via induction of epigenetic silencing. We will also discuss potential future therapeutic delivery and the challenges associated with progressing "block and lock" cure approaches as these move toward clinical trials.
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Affiliation(s)
| | | | - Stephen J. Kent
- Department of Microbiology and Immunology, Peter Doherty Institute, The University of Melbourne, Melbourne, VIC, Australia
- Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia
- ARC Centre for Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Parkville, VIC, Australia
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15
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Ait-Ammar A, Kula A, Darcis G, Verdikt R, De Wit S, Gautier V, Mallon PWG, Marcello A, Rohr O, Van Lint C. Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs. Front Microbiol 2020; 10:3060. [PMID: 32038533 PMCID: PMC6993040 DOI: 10.3389/fmicb.2019.03060] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/18/2019] [Indexed: 12/15/2022] Open
Abstract
One of the most explored therapeutic approaches aimed at eradicating HIV-1 reservoirs is the "shock and kill" strategy which is based on HIV-1 reactivation in latently-infected cells ("shock" phase) while maintaining antiretroviral therapy (ART) in order to prevent spreading of the infection by the neosynthesized virus. This kind of strategy allows for the "kill" phase, during which latently-infected cells die from viral cytopathic effects or from host cytolytic effector mechanisms following viral reactivation. Several latency reversing agents (LRAs) with distinct mechanistic classes have been characterized to reactivate HIV-1 viral gene expression. Some LRAs have been tested in terms of their potential to purge latent HIV-1 in vivo in clinical trials, showing that reversing HIV-1 latency is possible. However, LRAs alone have failed to reduce the size of the viral reservoirs. Together with the inability of the immune system to clear the LRA-activated reservoirs and the lack of specificity of these LRAs, the heterogeneity of the reservoirs largely contributes to the limited success of clinical trials using LRAs. Indeed, HIV-1 latency is established in numerous cell types that are characterized by distinct phenotypes and metabolic properties, and these are influenced by patient history. Hence, the silencing mechanisms of HIV-1 gene expression in these cellular and tissue reservoirs need to be better understood to rationally improve this cure strategy and hopefully reach clinical success.
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Affiliation(s)
- Amina Ait-Ammar
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Anna Kula
- Malopolska Centre of Biotechnology, Laboratory of Virology, Jagiellonian University, Krakow, Poland
| | - Gilles Darcis
- Infectious Diseases Department, Liège University Hospital, Liège, Belgium
| | - Roxane Verdikt
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Stephane De Wit
- Service des Maladies Infectieuses, CHU Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Virginie Gautier
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick W G Mallon
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin, Dublin, Ireland
| | - Alessandro Marcello
- Laboratory of Molecular Virology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Olivier Rohr
- Université de Strasbourg, EA7292, FMTS, IUT Louis Pasteur, Schiltigheim, France
| | - Carine Van Lint
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
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16
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Meås HZ, Haug M, Beckwith MS, Louet C, Ryan L, Hu Z, Landskron J, Nordbø SA, Taskén K, Yin H, Damås JK, Flo TH. Sensing of HIV-1 by TLR8 activates human T cells and reverses latency. Nat Commun 2020; 11:147. [PMID: 31919342 PMCID: PMC6952430 DOI: 10.1038/s41467-019-13837-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Accepted: 12/02/2019] [Indexed: 12/31/2022] Open
Abstract
During HIV infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that synthetic ligands of TLR8 boosted T cell receptor signaling, resulting in increased cytokine production and upregulation of surface activation markers. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, further promoted T helper cell differentiation towards Th1 and Th17. In addition, we found that endosomal HIV induced cytokine secretion from CD4+ T cells in a TLR8-specific manner. TLR8 engagement also enhanced HIV-1 replication and potentiated the reversal of latency in patient-derived T cells. The adjuvant TLR8 activity in T cells can contribute to viral dissemination in the lymph node and low-grade inflammation in HIV patients. In addition, it can potentially be exploited for therapeutic targeting and vaccine development.
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Affiliation(s)
- Hany Zekaria Meås
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Markus Haug
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Marianne Sandvold Beckwith
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Claire Louet
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Liv Ryan
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Zhenyi Hu
- School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, 100082, Beijing, China.,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Johannes Landskron
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Svein Arne Nordbø
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Medical Microbiology, St. Olavs Hospital, Trondheim, Norway
| | - Kjetil Taskén
- Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.,Department of Cancer Immunology, Institute of Cancer Research, Oslo University Hospital, Oslo, Norway.,K.G. Jebsen Centre for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Hang Yin
- School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, 100082, Beijing, China
| | - Jan Kristian Damås
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway
| | - Trude Helen Flo
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway. .,Department of Infectious Diseases, St. Olavs Hospital, Trondheim, Norway. .,Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Oslo, Norway.
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17
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Why and where an HIV cure is needed and how it might be achieved. Nature 2019; 576:397-405. [PMID: 31853080 DOI: 10.1038/s41586-019-1841-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 11/14/2019] [Indexed: 12/22/2022]
Abstract
Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.
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18
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Macedo AB, Novis CL, Bosque A. Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists. Front Immunol 2019; 10:2450. [PMID: 31681325 PMCID: PMC6804373 DOI: 10.3389/fimmu.2019.02450] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 10/01/2019] [Indexed: 01/04/2023] Open
Abstract
The elimination of both cellular and tissue latent reservoirs is a challenge toward a successful HIV cure. "Shock and Kill" are among the therapeutic strategies that have been more extensively studied to target these reservoirs. These strategies are aimed toward the reactivation of the latent reservoir using a latency-reversal agent (LRA) with the subsequent killing of the reactivated cell either by the cytotoxic arm of the immune system, including NK and CD8 T cells, or by viral cytopathic mechanisms. Numerous LRAs are currently being investigated in vitro, ex vivo as well as in vivo for their ability to reactivate and reduce latent reservoirs. Among those, several toll-like receptor (TLR) agonists have been shown to reactivate latent HIV. In humans, there are 10 TLRs that recognize different pathogen-associated molecular patterns. TLRs are present in several cell types, including CD4 T cells, the cell compartment that harbors the majority of the latent reservoir. Besides their ability to reactivate latent HIV, TLR agonists also increase immune activation and promote an antiviral response. These combined properties make TLR agonists unique among the different LRAs characterized to date. Additionally, some of these agonists have shown promise toward finding an HIV cure in animal models. When in combination with broadly neutralizing antibodies, TLR-7 agonists have shown to impact the SIV latent reservoir and delay viral rebound. Moreover, there are FDA-approved TLR agonists that are currently being investigated for cancer therapy and other diseases. All these has prompted clinical trials using TLR agonists either alone or in combination toward HIV eradication approaches. In this review, we provide an extensive characterization of the state-of-the-art of the use of TLR agonists toward HIV eradication strategies and the mechanism behind how TLR agonists target both cellular and tissue HIV reservoirs.
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Affiliation(s)
- Amanda B. Macedo
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, United States
| | - Camille L. Novis
- Department of Pathology, Division of Microbiology and Immunology, The University of Utah, Salt Lake City, UT, United States
| | - Alberto Bosque
- Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC, United States
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19
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Sadowski I, Hashemi FB. Strategies to eradicate HIV from infected patients: elimination of latent provirus reservoirs. Cell Mol Life Sci 2019; 76:3583-3600. [PMID: 31129856 PMCID: PMC6697715 DOI: 10.1007/s00018-019-03156-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/29/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023]
Abstract
35 years since identification of HIV as the causative agent of AIDS, and 35 million deaths associated with this disease, significant effort is now directed towards the development of potential cures. Current anti-retroviral (ART) therapies for HIV/AIDS can suppress virus replication to undetectable levels, and infected individuals can live symptom free so long as treatment is maintained. However, removal of therapy allows rapid re-emergence of virus from a highly stable reservoir of latently infected cells that exist as a barrier to elimination of the infection with current ART. Prospects of a cure for HIV infection are significantly encouraged by two serendipitous cases where individuals have entered remission following stem cell transplantation from compatible HIV-resistant donors. However, development of a routine cure that could become available to millions of infected individuals will require a means of specifically purging cells harboring latent HIV, preventing replication of latent provirus, or destruction of provirus genomes by gene editing. Elimination of latently infected cells will require a means of exposing this population, which may involve identification of a natural specific biomarker or therapeutic intervention to force their exposure by reactivation of virus expression. Accordingly, the proposed "Shock and Kill" strategy involves treatment with latency-reversing agents (LRA) to induce HIV provirus expression thus exposing these cells to killing by cellular immunity or apoptosis. Current efforts to enable this strategy are directed at developing improved combinations of LRA to produce broad and robust induction of HIV provirus and enhancing the elimination of cells where replication has been reactivated by targeted immune modulation. Alternative strategies may involve preventing re-emergence virus from latently infected cells by "Lock and Block" intervention, where transcription of provirus is inhibited to prevent virus spread or disruption of the HIV provirus genome by genome editing.
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Affiliation(s)
- Ivan Sadowski
- Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
| | - Farhad B Hashemi
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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20
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Stoszko M, Ne E, Abner E, Mahmoudi T. A broad drug arsenal to attack a strenuous latent HIV reservoir. Curr Opin Virol 2019; 38:37-53. [PMID: 31323521 DOI: 10.1016/j.coviro.2019.06.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/22/2019] [Accepted: 06/02/2019] [Indexed: 02/06/2023]
Abstract
HIV cure is impeded by the persistence of a strenuous reservoir of latent but replication competent infected cells, which remain unsusceptible to c-ART and unrecognized by the immune system for elimination. Ongoing progress in understanding the molecular mechanisms that control HIV transcription and latency has led to the development of strategies to either permanently inactivate the latent HIV infected reservoir of cells or to stimulate the virus to emerge out of latency, coupled to either induction of death in the infected reactivated cell or its clearance by the immune system. This review focuses on the currently explored and non-exclusive pharmacological strategies and their molecular targets that 1. stimulate reversal of HIV latency in infected cells by targeting distinct steps in the HIV-1 gene expression cycle, 2. exploit mechanisms that promote cell death and apoptosis to render the infected cell harboring reactivated virus more susceptible to death and/or elimination by the immune system, and 3. permanently inactivate any remaining latently infected cells such that c-ART can be safely discontinued.
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Affiliation(s)
- Mateusz Stoszko
- Department of Biochemistry, Erasmus University Medical Center, Ee634 PO Box 2040, 3000CA, Rotterdam, The Netherlands
| | - Enrico Ne
- Department of Biochemistry, Erasmus University Medical Center, Ee634 PO Box 2040, 3000CA, Rotterdam, The Netherlands
| | - Erik Abner
- Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Tokameh Mahmoudi
- Department of Biochemistry, Erasmus University Medical Center, Ee634 PO Box 2040, 3000CA, Rotterdam, The Netherlands.
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21
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Yamamoto T, Kanuma T, Takahama S, Okamura T, Moriishi E, Ishii KJ, Terahara K, Yasutomi Y. STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques. Sci Rep 2019; 9:5917. [PMID: 30976083 PMCID: PMC6459902 DOI: 10.1038/s41598-019-42253-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 03/20/2019] [Indexed: 02/06/2023] Open
Abstract
To achieve a functional cure for HIV, treatment regimens that eradicate latently HIV-infected cells must be established. For this, many groups have attempted to reactivate latently-infected cells to induce cytopathic effects and/or elicit cytotoxic T lymphocyte (CTL)/NK cell-mediated immune responses to kill these cells. We believe that not only the reactivation of latently-infected cells, but also the induction of strong CTL responses, would be required for this. Here, we used typical immune activators that target pattern recognition receptors (PRRs). For our experimental model, we identified eight SIV-infected cynomolgus monkeys that became natural controllers of viremia. Although plasma viral loads were undetectable, we could measure SIV-DNA by qPCR in peripheral blood mononuclear cells (PBMCs). Using these PBMCs, we screened 10 distinct PRR ligands to measure IFN-α and IFN-γ production. Among these, STING ligands, cGAMP and c-di-AMP, and the TLR7/8 agonist R848 markedly increased cytokine levels. Both R848 and STING ligands could reactivate latently-infected cells in both cynomolgus monkeys and human PBMCs in vitro. Furthermore, c-di-AMP increased the frequency of SIV Gag-specific CD8+ T cells including polyfunctional CD8+ T cells, as compared to that in untreated control or R848-treated cells. Together, STING ligands might be candidates for HIV treatment.
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Affiliation(s)
- Takuya Yamamoto
- Laboratory of Immunosenescence, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan. .,Center for AIDS Research, Kumamoto University, Kumamoto, 860-0811, Japan.
| | - Tomohiro Kanuma
- Laboratory of Immunosenescence, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.,Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan
| | - Shokichi Takahama
- Laboratory of Immunosenescence, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.,Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan
| | - Tomotaka Okamura
- Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan
| | - Eiko Moriishi
- Laboratory of Immunosenescence, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan
| | - Ken J Ishii
- Laboratory of Adjuvant Innovation, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, 567-0085, Japan.,Laboratory of Vaccine Science, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan
| | - Kazutaka Terahara
- Department of Immunology, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan
| | - Yasuhiro Yasutomi
- Tsukuba Primate Research Center, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, 305-0843, Japan
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22
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Abner E, Jordan A. HIV "shock and kill" therapy: In need of revision. Antiviral Res 2019; 166:19-34. [PMID: 30914265 DOI: 10.1016/j.antiviral.2019.03.008] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/08/2019] [Accepted: 03/17/2019] [Indexed: 01/05/2023]
Abstract
The implementation of antiretroviral therapy 23 years ago has rendered HIV infection clinically manageable. However, the disease remains incurable, since it establishes latent proviral reservoirs, which in turn can stochastically begin reproducing viral particles throughout the patient's lifetime. Viral latency itself depends in large part on the silencing environment of the infected host cell, which can be chemically manipulated. "Shock and kill" therapy intends to reverse proviral quiescence by inducing transcription with pharmaceuticals and allowing a combination of antiretroviral therapy, host immune clearance and HIV-cytolysis to remove latently infected cells, leading to a complete cure. Over 160 compounds functioning as latency-reversing agents (LRAs) have been identified to date, but none of the candidates has yet led to a promising functional cure. Furthermore, fundamental bioinformatic and clinical research from the past decade has highlighted the complexity and highly heterogeneous nature of the proviral reservoirs, shedding doubt on the "shock and kill" concept. Alternative therapies such as the HIV transcription-inhibiting "block and lock" strategy are therefore being considered. In this review we describe the variety of existing classes of LRAs, discuss their current drawbacks and highlight the potential for combinatorial "shocktail" therapies for potent proviral reactivation. We also suggest investigating LRAs with lesser-known mechanisms of action, and examine the feasibility of "block and lock" therapy.
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Affiliation(s)
- Erik Abner
- Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain
| | - Albert Jordan
- Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain.
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23
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Castro-Gonzalez S, Colomer-Lluch M, Serra-Moreno R. Barriers for HIV Cure: The Latent Reservoir. AIDS Res Hum Retroviruses 2018; 34:739-759. [PMID: 30056745 PMCID: PMC6152859 DOI: 10.1089/aid.2018.0118] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Thirty-five years after the identification of HIV-1 as the causative agent of AIDS, we are still in search of vaccines and treatments to eradicate this devastating infectious disease. Progress has been made in understanding the molecular pathogenesis of this infection, which has been crucial for the development of the current therapy regimens. However, despite their efficacy at limiting active viral replication, these drugs are unable to purge the latent reservoir: a pool of cells that harbor transcriptionally inactive, but replication-competent HIV-1 proviruses, and that represent the main barrier to eradicate HIV-1 from affected individuals. In this review, we discuss advances in the field that have allowed a better understanding of HIV-1 latency, including the diverse cell types that constitute the latent reservoir, factors influencing latency, tools to study HIV-1 latency, as well as current and prospective therapeutic approaches to target these latently infected cells, so a functional cure for HIV/AIDS can become a reality.
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Affiliation(s)
- Sergio Castro-Gonzalez
- Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas
| | - Marta Colomer-Lluch
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Ruth Serra-Moreno
- Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas
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Darcis G, Das AT, Berkhout B. Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies. Viruses 2018; 10:v10040157. [PMID: 29596334 PMCID: PMC5923451 DOI: 10.3390/v10040157] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 03/26/2018] [Accepted: 03/28/2018] [Indexed: 02/07/2023] Open
Abstract
Jan Svoboda studied aspects of viral latency, in particular with respect to disease induction by avian RNA tumor viruses, which were later renamed as part of the extended retrovirus family. The course of retroviral pathogenesis is intrinsically linked to their unique property of integrating the DNA copy of the retroviral genome into that of the host cell, thus forming the provirus. Retroviral latency has recently become of major clinical interest to allow a better understanding of why we can effectively block the human immunodeficiency virus type 1 (HIV-1) in infected individuals with antiviral drugs, yet never reach a cure. We will discuss HIV-1 latency and its direct consequence—the formation of long-lasting HIV-1 reservoirs. We next focus on one of the most explored strategies in tackling HIV-1 reservoirs—the “shock and kill” strategy—which describes the broadly explored pharmacological way of kicking the latent provirus, with subsequent killing of the virus-producing cell by the immune system. We furthermore present how the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system can be harnessed to reach the same objective by reactivating HIV-1 gene expression from latency. We will review the benefits and drawbacks of these different cure strategies.
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Affiliation(s)
- Gilles Darcis
- Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
- Infectious Diseases Department, Liège University Hospital, 4000 Liege, Belgium.
| | - Atze T Das
- Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Ben Berkhout
- Laboratory of Experimental Virology, Department of Medical Microbiology, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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Abstract
Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness; however, ART is not curative owing to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir so that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.
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Affiliation(s)
- Adam M Spivak
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84112
| | - Vicente Planelles
- Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84112;
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