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Gerg A, Dobrovolny HM. Quantifying Impact of HIV Receptor Surface Density Reveals Differences in Fusion Dynamics of HIV Strains. Viruses 2025; 17:583. [PMID: 40285025 PMCID: PMC12031222 DOI: 10.3390/v17040583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 04/04/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
Human Immunodeficiency Virus (HIV) Type-1 has been studied heavily for decades, yet one area that is still poorly understood is the virus' ability to cause cell-cell fusion. In HIV, the fusion process is mediated by viral surface glycoproteins that bind to CD4 cell receptors. This virus-mediated cell fusion creates multi-nucleated cells called syncytia that can affect infection dynamics. Syncytia formation is often studied using a cell-cell fusion assay, in which donor cells expressing the viral surface protein fuse with acceptor cells expressing the cell receptor. A mathematical model capable of reproducing the dynamics of the cell-cell fusion assay was recently developed and can be used to quantify changes in syncytia formation. In this study, we use this mathematical model to quantify the changes in syncytia formation in HIV as the surface density of the glycoproteins is varied. We find that we need to modify the model to explicitly include a density-dependent syncytia formation rate that allows us to capture the dynamics of the cell-cell fusion assay as the density of the glycoproteins changes. With this modification, we find that cell-cell fusion of the HXB2 strain, which uses the CXCR4 coreceptor, shows a threshold-like behavior, while cell-cell fusion of the Sf162 strain, which uses the CCR5 co-receptor, shows a more gradual change as surface density decreases.
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Affiliation(s)
| | - Hana M. Dobrovolny
- Department of Physics & Astronomy, Texas Christian University, Fort Worth, TX 76129, USA;
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2
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Janevska M, Witkowski W, Vermeire J, Borowicz M, Naessens E, Vanderstraeten H, Nauwynck H, Favoreel H, Verhasselt B. Impairment of endocytosis-related factors FNBP1L, ARHGAP24, and ATP6V1B1 increases HIV-1 entry into dendritic cells. J Virol 2025; 99:e0206624. [PMID: 40029073 PMCID: PMC11998494 DOI: 10.1128/jvi.02066-24] [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: 11/20/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025] Open
Abstract
HIV-1 infects several types of CD4+ cells. Among these, dendritic cells (DCs) are considered one of the first to encounter the virus upon sexual transmission. Expression of several restriction factors, of which SAMHD1 is well known, limits productive infection. Still, DCs are essential players in shaping adaptive immune responses that contribute heavily to the pathogenesis of HIV. Here, we set out to identify other factors that potentially contribute to the resistance of dendritic cells to HIV infection. Since endocytosis and the cytoskeleton impact HIV infection, we have put special emphasis on proteins implied in these pathways. In a selective, shRNA-mediated knockdown screen in primary monocyte-derived dendritic cells (MDDCs) infected with HIV in the presence of SAMHD1-disactivating Vpx containing virus-like particles, three proteins hampering HIV-1 infection were identified: FNBP1L, ARHGAP24, and ATP6V1B1. Findings of our research indicate that upon blocking of factors involved in endocytosis, increased viral entry is observed providing supportive evidence for endocytosis mostly being a dead-end entry pathway for HIV infection of MDDCs. Additional experiments show that changes in the cytoskeleton and endosomal pH that lead to impaired fluid-phase endocytosis and phagocytosis are responsible for these shifts in the phenotype observed.IMPORTANCEUnderstanding how HIV-1 interacts with dendritic cells (DCs) is pivotal in deciphering early viral transmission and immune evasion but is subject to a long-standing controversy in HIV virology. Therefore, the identification of endocytosis-related host factors as barriers to productive infection in DCs emphasizes the role of endocytosis as a restrictive pathway for viral entry. By disrupting these processes, we highlight a shift in the cellular environment that could influence viral entry and transmission. These findings challenge existing models of HIV-1 entry into DCs. New insights into how cellular pathways limit viral spread have implications for the development of strategies aimed to curb viral dissemination and reservoir formation. Whether the knockdown of the proteins described simply augments the efficiency of infection via existing pathways or opens additional routes for HIV-1 entry remains to be investigated.
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Affiliation(s)
- Marija Janevska
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
| | - Wojciech Witkowski
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
| | - Jolien Vermeire
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
| | - Marek Borowicz
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
| | - Evelien Naessens
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
- Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
| | - Hanne Vanderstraeten
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
| | - Hans Nauwynck
- Department of Parasitology, Virology and Immunology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
| | - Herman Favoreel
- Department of Parasitology, Virology and Immunology, Faculty of Veterinary Medicine, Ghent University, Ghent, Belgium
| | - Bruno Verhasselt
- Department of Diagnostic Sciences, Faculty of Medicine and Life Sciences, Ghent University, Ghent, Belgium
- Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium
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3
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Singh G, Mehra A, Arora S, Gugulothu D, Vora LK, Prasad R, Khatri DK. Exosome-mediated delivery and regulation in neurological disease progression. Int J Biol Macromol 2024; 264:130728. [PMID: 38467209 DOI: 10.1016/j.ijbiomac.2024.130728] [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: 12/08/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/13/2024]
Abstract
Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-β protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.
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Affiliation(s)
- Gurpreet Singh
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, India
| | - Ankit Mehra
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, India
| | - Sanchit Arora
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Delhi Pharmaceutical Sciences and Research University (DPSRU), M.B. Road, Pushp Vihar, Sector-3, New Delhi 110017, India
| | - Dalapathi Gugulothu
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research (DIPSAR), Delhi Pharmaceutical Sciences and Research University (DPSRU), M.B. Road, Pushp Vihar, Sector-3, New Delhi 110017, India.
| | - Lalitkumar K Vora
- School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, UK.
| | - Renuka Prasad
- Department of Anatomy, Korea University College of Medicine, Moonsuk Medical Research Building, 516, 5th floor, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Dharmendra Kumar Khatri
- Molecular and cellular neuroscience lab, Department of pharmacology and toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Hyderabad, India; Department of Pharmacology, Shobhaben Pratapbai Patel School of Pharmacy & Technology Management, SVKM's Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Mumbai 400056, India.
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4
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Urokinase plasminogen activator surface receptor restricts HIV-1 replication by blocking virion release from the cell membrane. Proc Natl Acad Sci U S A 2023; 120:e2212991120. [PMID: 36638209 PMCID: PMC9934069 DOI: 10.1073/pnas.2212991120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The urokinase-type plasminogen activator (uPA) system consists of the proteinase uPA, its receptor (PLAUR/uPAR). Under physiological conditions, uPA and PLAUR are predominantly expressed by blood cells, including neutrophils, monocytes, and macrophages, and play important roles in cell activation, adhesion, migration, and extravasation. Here, we report that PLAUR, which is highly expressed in macrophages and dendritic cells (DCs) but hardly expressed in CD4+ T cells, inhibits the release of HIV-1 progeny virions from the cell membrane. Silencing PLAUR markedly enhanced the transmission of HIV-1 in macrophages and DCs. We further demonstrated that PLAUR is localized at the cell membrane to block the release of HIV-1 virions. Interestingly, we found that uPA compromises the PLAUR-mediated inhibition to slightly enhance HIV-1 production in primary macrophages and DCs. In the absence of PLAUR, this enhanced effect induced by uPA is abrogated. In conclusion, PLAUR is a new anti-HIV-1 protein produced in both macrophages and DCs where it inhibits HIV-1 transmission. This discovery may provide a novel therapeutic target for combating HIV.
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Neuropilin-1, a myeloid cell-specific protein, is an inhibitor of HIV-1 infectivity. Proc Natl Acad Sci U S A 2022; 119:2114884119. [PMID: 34987100 PMCID: PMC8764665 DOI: 10.1073/pnas.2114884119] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2021] [Indexed: 12/13/2022] Open
Abstract
Myeloid lineage cells such as macrophages and dendritic cells (DCs), targeted by HIV-1, are important vehicles for virus dissemination through the body as well as viral reservoirs. Compared to activated lymphocytes, myeloid cells are collectively more resistant to HIV-1 infection. Here we report that NRP-1, encoding transmembrane protein neuropilin-1, is highly expressed in macrophages and DCs but not CD4+ T cells, serving as an anti-HIV factor to inhibit the infectivity of HIV-1 progeny virions. Silencing NRP-1 enhanced the transmission of HIV-1 in macrophages and DCs significantly and increased the infectivity of the virions produced by these cells. We further demonstrated that NRP-1 was packaged into the progeny virions to inhibit their ability to attach to target cells, thus reducing the infectivity of the virions. These data indicate that NRP-1 is a newly identified antiviral protein highly produced in both macrophages and DCs that inhibit HIV-1 infectivity; thus, NRP-1 may be a novel therapeutic strategy for the treatment of HIV-1 infection.
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Perez-Zsolt D, Raïch-Regué D, Muñoz-Basagoiti J, Aguilar-Gurrieri C, Clotet B, Blanco J, Izquierdo-Useros N. HIV-1 trans-Infection Mediated by DCs: The Tip of the Iceberg of Cell-to-Cell Viral Transmission. Pathogens 2021; 11:39. [PMID: 35055987 PMCID: PMC8778849 DOI: 10.3390/pathogens11010039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
HIV-1 cell-to-cell transmission is key for an effective viral replication that evades immunity. This highly infectious mechanism is orchestrated by different cellular targets that utilize a wide variety of processes to efficiently transfer HIV-1 particles. Dendritic cells (DCs) are the most potent antigen presenting cells that initiate antiviral immune responses, but are also the cells with highest capacity to transfer HIV-1. This mechanism, known as trans-infection, relies on the capacity of DCs to capture HIV-1 particles via lectin receptors such as the sialic acid-binding I-type lectin Siglec-1/CD169. The discovery of the molecular interaction of Siglec-1 with sialylated lipids exposed on HIV-1 membranes has enlightened how this receptor can bind to several enveloped viruses. The outcome of these interactions can either mount effective immune responses, boost the productive infection of DCs and favour innate sensing, or fuel viral transmission via trans-infection. Here we review these scenarios focusing on HIV-1 and other enveloped viruses such as Ebola virus or SARS-CoV-2.
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Affiliation(s)
- Daniel Perez-Zsolt
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
| | - Dàlia Raïch-Regué
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
| | - Jordana Muñoz-Basagoiti
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
| | - Carmen Aguilar-Gurrieri
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
| | - Bonaventura Clotet
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
- Infectious Diseases and Immunity Department, Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
| | - Julià Blanco
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
- Infectious Diseases and Immunity Department, Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain
- Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916 Badalona, Spain
| | - Nuria Izquierdo-Useros
- IrsiCaixa AIDS Research Institute, Can Ruti Campus, 08916 Badalona, Spain; (D.P.-Z.); (D.R.-R.); (J.M.-B.); (C.A.-G.); (B.C.); (J.B.)
- Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916 Badalona, Spain
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7
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Cattin A, Wacleche VS, Fonseca Do Rosario N, Marchand LR, Dias J, Gosselin A, Cohen EA, Estaquier J, Chomont N, Routy JP, Ancuta P. RALDH Activity Induced by Bacterial/Fungal Pathogens in CD16 + Monocyte-Derived Dendritic Cells Boosts HIV Infection and Outgrowth in CD4 + T Cells. THE JOURNAL OF IMMUNOLOGY 2021; 206:2638-2651. [PMID: 34031148 DOI: 10.4049/jimmunol.2001436] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/30/2021] [Indexed: 12/12/2022]
Abstract
HIV reservoirs persist in gut-homing CD4+ T cells of people living with HIV and receiving antiretroviral therapy, but the antigenic specificity of such reservoirs remains poorly documented. The imprinting for gut homing is mediated by retinoic acid (RA), a vitamin A-derived metabolite produced by dendritic cells (DCs) exhibiting RA-synthesizing (RALDH) activity. RALDH activity in DCs can be induced by TLR2 ligands, such as bacterial peptidoglycans and fungal zymosan. Thus, we hypothesized that bacterial/fungal pathogens triggering RALDH activity in DCs fuel HIV reservoir establishment/outgrowth in pathogen-reactive CD4+ T cells. Our results demonstrate that DCs derived from intermediate/nonclassical CD16+ compared with classical CD16- monocytes exhibited superior RALDH activity and higher capacity to transmit HIV infection to autologous Staphylococcus aureus-reactive T cells. Exposure of total monocyte-derived DCs (MDDCs) to S. aureus lysates as well as TLR2 (zymosan and heat-killed preparation of Listeria monocytogenes) and TLR4 (LPS) agonists but not CMV lysates resulted in a robust upregulation of RALDH activity. MDDCs loaded with S. aureus or zymosan induced the proliferation of T cells with a CCR5+integrin β7+CCR6+ phenotype and efficiently transmitted HIV infection to these T cells via RALDH/RA-dependent mechanisms. Finally, S. aureus- and zymosan-reactive CD4+ T cells of antiretroviral therapy-treated people living with HIV carried replication-competent integrated HIV-DNA, as demonstrated by an MDDC-based viral outgrowth assay. Together, these results support a model in which bacterial/fungal pathogens in the gut promote RALDH activity in MDDCs, especially in CD16+ MDDCs, and subsequently imprint CD4+ T cells with gut-homing potential and HIV permissiveness. Thus, nonviral pathogens play key roles in fueling HIV reservoir establishment/outgrowth via RALDH/RA-dependent mechanisms that may be therapeutically targeted.
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Affiliation(s)
- Amélie Cattin
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Vanessa Sue Wacleche
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | | | | | - Jonathan Dias
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Annie Gosselin
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Eric A Cohen
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.,Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada
| | - Jérôme Estaquier
- Université Laval, Quebec City, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université Laval, Quebec City, Quebec, Canada
| | - Nicolas Chomont
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.,Chronic Viral Illness Service, McGill University Health Centre, Montreal, Quebec, Canada; and.,Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Petronela Ancuta
- Faculté de Médecine, Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec, Canada; .,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
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8
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Hartana CA, Rassadkina Y, Gao C, Martin-Gayo E, Walker BD, Lichterfeld M, Yu XG. Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers. J Clin Invest 2021; 131:146136. [PMID: 33938445 PMCID: PMC8087208 DOI: 10.1172/jci146136] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 03/11/2021] [Indexed: 12/24/2022] Open
Abstract
Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell-mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabolic state of mDCs, likely through epigenetic mechanisms involving H3K27ac enrichment at an intronic enhancer in the RPTOR gene locus, the main component of the mammalian target of rapamycin complex 1 (mTORC1). Together, these results suggest a role of MIR4435-2HG for enhancing immunometabolic activities of mDCs in ECs through targeted epigenetic modifications of a member of the mTOR signaling pathway.
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Affiliation(s)
| | | | - Ce Gao
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
| | - Enrique Martin-Gayo
- Immunology Unit, Universidad Autónoma de Madrid, Hospital Universitario la Princesa, Madrid, Spain
| | - Bruce D. Walker
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Institute for Medical Engineering and Sciences, and
- Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Mathias Lichterfeld
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Infectious Disease Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Xu G. Yu
- Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA
- Infectious Disease Division, Brigham and Women’s Hospital, Boston, Massachusetts, USA
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Abstract
The innate immune system is comprised of both cellular and humoral players that recognise and eradicate invading pathogens. Therefore, the interplay between retroviruses and innate immunity has emerged as an important component of viral pathogenesis. HIV-1 infection in humans that results in hematologic abnormalities and immune suppression is well represented by changes in the CD4/CD8 T cell ratio and consequent cell death causing CD4 lymphopenia. The innate immune responses by mucosal barriers such as complement, DCs, macrophages, and NK cells as well as cytokine/chemokine profiles attain great importance in acute HIV-1 infection, and thus, prevent mucosal capture and transmission of HIV-1. Conversely, HIV-1 has evolved to overcome innate immune responses through RNA-mediated rapid mutations, pathogen-associated molecular patterns (PAMPs) modification, down-regulation of NK cell activity and complement receptors, resulting in increased secretion of inflammatory factors. Consequently, epithelial tissues lining up female reproductive tract express innate immune sensors including anti-microbial peptides responsible for forming primary barriers and have displayed an effective potent anti-HIV activity during phase I/II clinical trials.
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Leroy H, Han M, Woottum M, Bracq L, Bouchet J, Xie M, Benichou S. Virus-Mediated Cell-Cell Fusion. Int J Mol Sci 2020; 21:E9644. [PMID: 33348900 PMCID: PMC7767094 DOI: 10.3390/ijms21249644] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 02/07/2023] Open
Abstract
Cell-cell fusion between eukaryotic cells is a general process involved in many physiological and pathological conditions, including infections by bacteria, parasites, and viruses. As obligate intracellular pathogens, viruses use intracellular machineries and pathways for efficient replication in their host target cells. Interestingly, certain viruses, and, more especially, enveloped viruses belonging to different viral families and including human pathogens, can mediate cell-cell fusion between infected cells and neighboring non-infected cells. Depending of the cellular environment and tissue organization, this virus-mediated cell-cell fusion leads to the merge of membrane and cytoplasm contents and formation of multinucleated cells, also called syncytia, that can express high amount of viral antigens in tissues and organs of infected hosts. This ability of some viruses to trigger cell-cell fusion between infected cells as virus-donor cells and surrounding non-infected target cells is mainly related to virus-encoded fusion proteins, known as viral fusogens displaying high fusogenic properties, and expressed at the cell surface of the virus-donor cells. Virus-induced cell-cell fusion is then mediated by interactions of these viral fusion proteins with surface molecules or receptors involved in virus entry and expressed on neighboring non-infected cells. Thus, the goal of this review is to give an overview of the different animal virus families, with a more special focus on human pathogens, that can trigger cell-cell fusion.
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Affiliation(s)
- Héloïse Leroy
- Institut Cochin, Inserm U1016, 75014 Paris, France; (H.L.); (M.H.); (M.W.)
- Centre National de la Recherche Scientifique CNRS, UMR8104, 75014 Paris, France
- Faculty of Health, University of Paris, 75014 Paris, France
| | - Mingyu Han
- Institut Cochin, Inserm U1016, 75014 Paris, France; (H.L.); (M.H.); (M.W.)
- Centre National de la Recherche Scientifique CNRS, UMR8104, 75014 Paris, France
- Faculty of Health, University of Paris, 75014 Paris, France
| | - Marie Woottum
- Institut Cochin, Inserm U1016, 75014 Paris, France; (H.L.); (M.H.); (M.W.)
- Centre National de la Recherche Scientifique CNRS, UMR8104, 75014 Paris, France
- Faculty of Health, University of Paris, 75014 Paris, France
| | - Lucie Bracq
- Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland;
| | - Jérôme Bouchet
- Laboratory Orofacial Pathologies, Imaging and Biotherapies UR2496, University of Paris, 92120 Montrouge, France;
| | - Maorong Xie
- Division of Infection and Immunity, University College London, London WC1E 6BT, UK;
| | - Serge Benichou
- Institut Cochin, Inserm U1016, 75014 Paris, France; (H.L.); (M.H.); (M.W.)
- Centre National de la Recherche Scientifique CNRS, UMR8104, 75014 Paris, France
- Faculty of Health, University of Paris, 75014 Paris, France
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11
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Kardani K, Basimi P, Fekri M, Bolhassani A. Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development. Expert Rev Clin Pharmacol 2020; 13:1001-1046. [PMID: 32838584 DOI: 10.1080/17512433.2020.1814743] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.
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Affiliation(s)
- Kimia Kardani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Parya Basimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Mehrshad Fekri
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
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12
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Benjelloun F, Quillay H, Cannou C, Marlin R, Madec Y, Fernandez H, Chrétien F, Le Grand R, Barré-Sinoussi F, Nugeyre MT, Menu E. Activation of Toll-Like Receptors Differentially Modulates Inflammation in the Human Reproductive Tract: Preliminary Findings. Front Immunol 2020; 11:1655. [PMID: 32849571 PMCID: PMC7417306 DOI: 10.3389/fimmu.2020.01655] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 06/22/2020] [Indexed: 12/15/2022] Open
Abstract
The female reproductive tract (FRT) is the main site of entry of sexually transmitted infections (STIs). Toll-like receptors (TLRs) that recognize pathogenic motifs are widely expressed in the FRT. TLR stimulation induces immune activation and local production of inflammatory mediators. In the FRT, this response should also be compatible with reproductive functions and symbiosis with host microbiota. With a view to develop efficient mucosal vaccines to prevent STI acquisition, the role of TLR ligands in the FRT needs to be explored. We have therefore investigated the cytokine profiles of the different compartments of the FRT (vagina, endocervix, ectocervix, and uterus) before and after stimulation of mononuclear cells from human tissue specimens. The comparison with PBMCs allowed us to highlight the FRT specificities. We first characterized the main immune cell populations in each compartment and observed that their distribution was different through the compartments. The CD45+ cells represented a maximum of 11% in the FRT in contrast to 96% in PBMCs. We identified two main populations among the CD45+ cells in the four compartments of the FRT: CD3+ T cells (CD4+ and CD8+) and CD14+ APCs. B cell populations (CD19+) were much less frequent than T cells in all the FRT regions and were equally distributed. NK CD56+ cells were detected in all compartments and were more abundant in the uterus. Stimulation of the mononuclear cells was then performed with TLR agonists: R848 for TLR7/8, Poly I:C for TLR3, LPS for TLR4 and ODN CpG for TLR9. Cytokine levels in unstimulated cultures of cells isolated from all FRT compartments were higher than in cultures of unstimulated PBMCs. In contrast, after stimulation with TLR agonists, cytokine responses induced by TLR agonists were moderate in the FRT and significantly lower than in PBMCs. These responses were varied with different TLR ligands and FRT compartments. The cytokine profile induced by TLR activation in the FRT supports the role of these tissues in genital anti-microbial immunity and in the control of inflammation while allowing maintenance of its reproductive function.
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Affiliation(s)
- Fahd Benjelloun
- MISTIC Team, Virology Department, Institut Pasteur, Paris, France.,Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
| | - Héloïse Quillay
- MISTIC Team, Virology Department, Institut Pasteur, Paris, France.,Paris Diderot University, Sorbonne Paris Cité, Cellule Pasteur, Paris, France
| | - Claude Cannou
- MISTIC Team, Virology Department, Institut Pasteur, Paris, France.,Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
| | - Romain Marlin
- Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
| | - Yoann Madec
- Emerging Diseases Epidemiology Unit, Institut Pasteur, Paris, France
| | - Hervé Fernandez
- Bicêtre Hospital, AP-HP, Gynecology-Obstetrics Service, Le Kremlin-Bicêtre, France
| | - Fabrice Chrétien
- Experimental Neuropathology Unit, Institut Pasteur, Paris, France
| | - Roger Le Grand
- Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
| | | | - Marie-Thérèse Nugeyre
- MISTIC Team, Virology Department, Institut Pasteur, Paris, France.,Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
| | - Elisabeth Menu
- MISTIC Team, Virology Department, Institut Pasteur, Paris, France.,Université Paris-Saclay, Inserm U1184, CEA, Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (ImVA-HB), IDMIT Department, IBFJ, Fontenay-Aux-Roses, France
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13
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Kulkarni R, Jiang S, Birrane G, Prasad A. Lymphocyte-specific protein 1 (LSP1) regulates bone marrow stromal cell antigen 2 (BST-2)-mediated intracellular trafficking of HIV-1 in dendritic cells. FEBS Lett 2020; 594:1947-1959. [PMID: 32279313 DOI: 10.1002/1873-3468.13788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
Human immunodeficiency virus type 1 (HIV-1) subverts intracellular trafficking pathways to avoid its degradation and elimination, thereby enhancing its survival and spread. The molecular mechanisms involved in intracellular transport of HIV-1 are not yet fully defined. We demonstrate that the actin-binding protein lymphocyte-specific protein 1 (LSP1) interacts with the interferon-inducible protein bone marrow stromal antigen 2 (BST-2) in dendritic cells (DCs) to facilitate both endocytosis of surface-bound HIV-1 and the formation of early endosomes. Analysis of the molecular interaction between LSP1 and BST-2 reveals that the N terminus of LSP1 interacts with BST-2. Overall, we identify a novel mechanism of intracellular trafficking of HIV-1 in DCs centering on the LSP1/BST-2 complex. We also show that the HIV-1 accessory protein Vpu subverts this pathway by inducing proteasomal degradation of LSP1, augmenting cell-cell transmission of HIV-1.
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Affiliation(s)
- Rutuja Kulkarni
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Shuxian Jiang
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Gabriel Birrane
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Anil Prasad
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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14
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Identification of Host Trafficking Genes Required for HIV-1 Virological Synapse Formation in Dendritic Cells. J Virol 2020; 94:JVI.01597-19. [PMID: 32075937 PMCID: PMC7163131 DOI: 10.1128/jvi.01597-19] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 02/04/2020] [Indexed: 01/15/2023] Open
Abstract
The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo. Dendritic cells (DCs) are one of the earliest targets of HIV-1 infection acting as a “Trojan horse,” concealing the virus from the innate immune system and delivering it to T cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput small interfering RNA screen targeting membrane trafficking proteins was performed in monocyte-derived DCs. We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus’s ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DCs that is exploited by HIV-1 to traffic to the VS. IMPORTANCE The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo.
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15
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Lumngwena EN, Abrahams B, Shuping L, Cicala C, Arthos J, Woodman Z. Selective transmission of some HIV-1 subtype C variants might depend on Envelope stimulating dendritic cells to secrete IL-10. PLoS One 2020; 15:e0227533. [PMID: 31978062 PMCID: PMC6980567 DOI: 10.1371/journal.pone.0227533] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 12/20/2019] [Indexed: 11/21/2022] Open
Abstract
Envelope (Env) phenotype(s) that provide transmitted founders (TF) with a selective advantage during HIV-1 transmission would be the ideal target for preventative therapy. We generated Env clones from four individuals infected with a single virus and one participant infected with multiple variants at transmission and compared phenotype with matched Envs from chronic infection (CI). When we determined whether pseudovirus (PSV) of the five TF and thirteen matched CI Env clones differed in their ability to 1) enter TZM-bl cells, 2) bind DC-SIGN, and 3) trans-infect CD4+ cells there was no association between time post-infection and variation in Env phenotype. However, when we compared the ability of PSV to induce monocyte-derived dendritic cells (MDDCs) to secrete Interleukin-10 (IL-10), we found that only TF Envs from single variant transmission cases induced MDDCs to secrete either higher or similar levels of IL-10 as the CI clones. Furthermore, interaction between MDDC DC-SIGN and Env was required for secretion of IL-10. When variants were grouped according to time post-infection, TF PSV induced the release of higher levels of IL-10 than their CI counterparts although this relationship varied across MDDC donors. The selection of variants during transmission is therefore likely a complex event dependent on both virus and host genetics. Our findings suggest that, potentially due to overall variation in N-glycosylation across variants, nuanced differences in binding of TF Env to DC-SIGN might trigger alternative DC immune responses (IRs) in the female genital tract (FGT) that favour HIV-1 survival and facilitate transmission.
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Affiliation(s)
- Evelyn Ngwa Lumngwena
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- Institute for Medical Research and Medicinal Plants studies (IMPM), Ministry of Scientific Research and Innovation (MINRESI), Yaounde, Cameroon
- * E-mail: (ZW); (ENL)
| | - Bianca Abrahams
- Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Liliwe Shuping
- National Institute for Communicable Diseases, National Health Laboratory Services, Johannesburg, South Africa
| | - Claudia Cicala
- National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, United States of America
| | - James Arthos
- National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, United States of America
| | - Zenda Woodman
- Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- * E-mail: (ZW); (ENL)
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16
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Nijmeijer BM, Geijtenbeek TBH. Negative and Positive Selection Pressure During Sexual Transmission of Transmitted Founder HIV-1. Front Immunol 2019; 10:1599. [PMID: 31354736 PMCID: PMC6635476 DOI: 10.3389/fimmu.2019.01599] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 06/26/2019] [Indexed: 12/21/2022] Open
Abstract
Sexual transmission of HIV-1 consists of processes that exert either positive or negative selection pressure on the virus. The sum of these selection pressures lead to the transmission of only one specific HIV-1 strain, termed the transmitted founder virus. Different dendritic cell subsets are abundantly present at mucosal sites and, interestingly, these DC subsets exert opposite pressure on viral selection during sexual transmission. In this review we describe receptors and cellular compartments in DCs that are involved in HIV-1 communication leading to either viral restriction by the host or further dissemination to establish a long-lived reservoir. We discuss the current understanding of host antiretroviral restriction factors against HIV-1 and specifically against the HIV-1 transmitted founder virus. We will also discuss potential clinical implications for exploiting these intrinsic restriction factors in developing novel therapeutic targets. A better understanding of these processes might help in developing strategies against HIV-1 infections by targeting dendritic cells.
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Affiliation(s)
- Bernadien M Nijmeijer
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, Netherlands
| | - Teunis B H Geijtenbeek
- Department of Experimental Immunology, Amsterdam University Medical Centers, Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, Netherlands
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17
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Ganesan M, Poluektova LY, Kharbanda KK, Osna NA. Liver as a target of human immunodeficiency virus infection. World J Gastroenterol 2018; 24:4728-4737. [PMID: 30479460 PMCID: PMC6235802 DOI: 10.3748/wjg.v24.i42.4728] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/10/2018] [Accepted: 10/21/2018] [Indexed: 02/06/2023] Open
Abstract
Liver injury is a characteristic feature of human immunodeficiency virus (HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy (ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIV-related liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression.
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Affiliation(s)
- Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Larisa Y Poluektova
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, United States
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18
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Bayliss RJ, Piguet V. Masters of manipulation: Viral modulation of the immunological synapse. Cell Microbiol 2018; 20:e12944. [PMID: 30123959 PMCID: PMC6492149 DOI: 10.1111/cmi.12944] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/01/2018] [Accepted: 08/14/2018] [Indexed: 02/06/2023]
Abstract
In order to thrive, viruses have evolved to manipulate host cell machinery for their own benefit. One major obstacle faced by pathogens is the immunological synapse. To enable efficient replication and latency in immune cells, viruses have developed a range of strategies to manipulate cellular processes involved in immunological synapse formation to evade immune detection and control T-cell activation. In vitro, viruses such as human immunodeficiency virus 1 and human T-lymphotropic virus type 1 utilise structures known as virological synapses to aid transmission of viral particles from cell to cell in a process termed trans-infection. The formation of the virological synapse provides a gateway for virus to be transferred between cells avoiding the extracellular space, preventing antibody neutralisation or recognition by complement. This review looks at how viruses are able to subvert intracellular signalling to modulate immune function to their advantage and explores the role synapse formation has in viral persistence and cell-to-cell transmission.
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Affiliation(s)
- Rebecca J. Bayliss
- Division of Infection and Immunity, School of MedicineCardiff UniversityCardiffUK
| | - Vincent Piguet
- Division of Infection and Immunity, School of MedicineCardiff UniversityCardiffUK
- Division of Dermatology, Department of MedicineUniversity of TorontoTorontoOntarioCanada
- Division of DermatologyWomen's College HospitalTorontoOntarioCanada
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19
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Shimauchi T, Caucheteux S, Finsterbusch K, Turpin J, Blanchet F, Ladell K, Triantafilou K, Czubala M, Tatsuno K, Easter T, Ahmed Z, Bayliss R, Hakobyan S, Price DA, Tokura Y, Piguet V. Dendritic Cells Promote the Spread of Human T-Cell Leukemia Virus Type 1 via Bidirectional Interactions with CD4 + T Cells. J Invest Dermatol 2018; 139:157-166. [PMID: 30048652 DOI: 10.1016/j.jid.2018.06.188] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 05/25/2018] [Accepted: 06/12/2018] [Indexed: 12/14/2022]
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) propagates within and between individuals via cell-to-cell transmission, and primary infection typically occurs across juxtaposed mucosal surfaces during breastfeeding or sexual intercourse. It is therefore likely that dendritic cells (DCs) are among the first potential targets for HTLV-1. However, it remains unclear how DCs contribute to virus transmission and dissemination in the early stages of infection. We show that an HTLV-1-infected cell line (MT-2) and naturally infected CD4+ T cells transfer p19+ viral particles to the surface of allogeneic DCs via cell-to-cell contacts. Similarly organized cell-to-cell contacts also facilitate DC-mediated transfer of HTLV-1 to autologous CD4+ T cells. These findings shed light on the cellular structures involved in anterograde and retrograde transmission and suggest a key role for DCs in the natural history and pathogenesis of HTLV-1 infection.
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Affiliation(s)
- Takatoshi Shimauchi
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Stephan Caucheteux
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Katja Finsterbusch
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Jocelyn Turpin
- Section of Virology, Department of Medicine, Imperial College London, London, UK
| | - Fabien Blanchet
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Kristin Ladell
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Kathy Triantafilou
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Magdalena Czubala
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Kazuki Tatsuno
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tammy Easter
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Zahra Ahmed
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Rebecca Bayliss
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Svetlana Hakobyan
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - David A Price
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK
| | - Yoshiki Tokura
- Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Vincent Piguet
- Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; Division of Dermatology, Women's College Hospital, Toronto, Canada; Division of Dermatology, Department of Medicine, University of Toronto, Canada.
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20
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Caucheteux S, Piguet V. Vaginal epidermal dendritic cells: defense against HIV-1 or a safe haven? J Clin Invest 2018; 128:3228-3230. [PMID: 29985165 DOI: 10.1172/jci121744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Langerhans cells (LCs) are likely among the first targets of HIV-1 infection due to their localization in mucosal tissues. In their recent work, Pena-Cruz and colleagues were able to study HIV-1 infection in vaginal epithelial DCs (VEDCs), termed CD1a+ VEDCs. They show that VEDCs are distinct from other blood- and tissue-derived DCs or LCs because they express the protein langerin but not the lectin receptor DC-SIGN, and they do not have Birbeck granules. The results from this study indicate that HIV-1 using CXCR4 replicates poorly in VEDCs but that a higher replication for HIV-1 using CCR5 strains is supported by VDECs. Furthermore, Pena-Cruz and colleagues demonstrate that VDECs can represent a viral reservoir in HIV-1-infected virologically suppressed women. As such, VDECs may represent another sanctuary of viral persistence and can be an additional obstacle to viral eradication.
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Affiliation(s)
- Stephan Caucheteux
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vincent Piguet
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Division of Dermatology, Women's College Hospital, Toronto, Ontario, Canada
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21
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Anderson M, Kashanchi F, Jacobson S. Role of Exosomes in Human Retroviral Mediated Disorders. J Neuroimmune Pharmacol 2018; 13:279-291. [PMID: 29656370 DOI: 10.1007/s11481-018-9784-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 03/15/2018] [Indexed: 02/07/2023]
Abstract
Retroviruses comprise an ancient and varied group of viruses with the unique ability to integrate DNA from an RNA transcript into the genome, a subset of which are able to integrate in humans. The timing of these integrations during human history has dictated whether these viruses have remained exogenous and given rise to various human diseases or have become inseparable from the host genome (endogenous retroviruses). Given the ability of retroviruses to integrate into the host and subsequently co-opt host cellular process for viral propagation, retroviruses have been shown to be closely associated with several cellular processes including exosome formation. Exosomes are 30-150 nm unilamellar extracellular vesicles that originate from intraluminal vesicles (ILVs) that form in the endosomal compartment. Exosomes have been shown to be important in intercellular communication and immune cell function. Almost every cell type studied has been shown to produce these types of vesicles, with the cell type dictating the contents, which include proteins, mRNA, and miRNAs. Importantly, recent evidence has shown that infection by viruses, including retroviruses, alter the contents and subsequent function of produced exosomes. In this review, we will discuss the important retroviruses associated with human health and disease. Furthermore, we will delve into the impact of exosome formation and manipulation by integrated retroviruses on human health, survival, and human retroviral disease pathogenesis.
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Affiliation(s)
- Monique Anderson
- National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Viral Immunology Section, National Institutes of Health, Bethesda, MD, 20892, USA. .,Department of Pathology, Molecular and Cellular Basis of Disease Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
| | - Fatah Kashanchi
- National Center for Biodefense and Infectious Disease, Laboratory of Molecular Virology, George Mason University, Manassas, VA, 20110, USA
| | - Steven Jacobson
- National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Viral Immunology Section, National Institutes of Health, Bethesda, MD, 20892, USA
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22
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Abstract
While HIV-1 infection of target cells with cell-free viral particles has been largely documented, intercellular transmission through direct cell-to-cell contact may be a predominant mode of propagation in host. To spread, HIV-1 infects cells of the immune system and takes advantage of their specific particularities and functions. Subversion of intercellular communication allows to improve HIV-1 replication through a multiplicity of intercellular structures and membrane protrusions, like tunneling nanotubes, filopodia, or lamellipodia-like structures involved in the formation of the virological synapse. Other features of immune cells, like the immunological synapse or the phagocytosis of infected cells are hijacked by HIV-1 and used as gateways to infect target cells. Finally, HIV-1 reuses its fusogenic capacity to provoke fusion between infected donor cells and target cells, and to form infected syncytia with high capacity of viral production and improved capacities of motility or survival. All these modes of cell-to-cell transfer are now considered as viral mechanisms to escape immune system and antiretroviral therapies, and could be involved in the establishment of persistent virus reservoirs in different host tissues.
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Affiliation(s)
- Lucie Bracq
- Inserm U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France.,International Associated Laboratory (LIA VirHost), Institut Pasteur Shanghai-Chinese Academy of Sciences, Shanghai, China.,International Associated Laboratory (LIA VirHost), CNRS, Université Paris-Descartes, Institut Pasteur, Paris, France
| | - Maorong Xie
- Inserm U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France.,International Associated Laboratory (LIA VirHost), CNRS, Université Paris-Descartes, Institut Pasteur, Paris, France
| | - Serge Benichou
- Inserm U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France.,International Associated Laboratory (LIA VirHost), Institut Pasteur Shanghai-Chinese Academy of Sciences, Shanghai, China.,International Associated Laboratory (LIA VirHost), CNRS, Université Paris-Descartes, Institut Pasteur, Paris, France
| | - Jérôme Bouchet
- Inserm U1016, Institut Cochin, Paris, France.,CNRS, UMR8104, Paris, France.,Université Paris-Descartes, Sorbonne Paris-Cité, Paris, France.,International Associated Laboratory (LIA VirHost), CNRS, Université Paris-Descartes, Institut Pasteur, Paris, France
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The Biology of Monocytes and Dendritic Cells: Contribution to HIV Pathogenesis. Viruses 2018; 10:v10020065. [PMID: 29415518 PMCID: PMC5850372 DOI: 10.3390/v10020065] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 02/01/2018] [Accepted: 02/03/2018] [Indexed: 02/07/2023] Open
Abstract
Myeloid cells such as monocytes, dendritic cells (DC) and macrophages (MΦ) are key components of the innate immune system contributing to the maintenance of tissue homeostasis and the development/resolution of immune responses to pathogens. Monocytes and DC, circulating in the blood or infiltrating various lymphoid and non-lymphoid tissues, are derived from distinct bone marrow precursors and are typically short lived. Conversely, recent studies revealed that subsets of tissue resident MΦ are long-lived as they originate from embryonic/fetal precursors that have the ability to self-renew during the life of an individual. Pathogens such as the human immunodeficiency virus type 1 (HIV-1) highjack the functions of myeloid cells for viral replication (e.g., MΦ) or distal dissemination and cell-to-cell transmission (e.g., DC). Although the long-term persistence of HIV reservoirs in CD4+ T-cells during viral suppressive antiretroviral therapy (ART) is well documented, the ability of myeloid cells to harbor replication competent viral reservoirs is still a matter of debate. This review summarizes the current knowledge on the biology of monocytes and DC during homeostasis and in the context of HIV-1 infection and highlights the importance of future studies on long-lived resident MΦ to HIV persistence in ART-treated patients.
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Naumenko V, Turk M, Jenne CN, Kim SJ. Neutrophils in viral infection. Cell Tissue Res 2018; 371:505-516. [PMID: 29327081 DOI: 10.1007/s00441-017-2763-0] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 11/28/2017] [Indexed: 12/20/2022]
Abstract
Neutrophils are the first wave of recruited immune cells to sites of injury or infection and are crucial players in controlling bacterial and fungal infections. Although the role of neutrophils during bacterial or fungal infections is well understood, their impact on antiviral immunity is much less studied. Furthermore, neutrophil function in tumor pathogenesis and cancer treatment has recently received much attention, particularly within the context of oncolytic virus infection where neutrophils produce antitumor cytokines and enhance oncolysis. In this review, multiple functions of neutrophils in viral infections and immunity are discussed. Understanding the role of neutrophils during viral infection may provide insight into the pathogenesis of virus infections and the outcome of virus-based therapies.
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Affiliation(s)
- Victor Naumenko
- Department of Microbiology, Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3330 Hospital Drive N.W, Calgary, Alberta, T2N 4N1, Canada.,National University of Science and Technology "MISIS", Leninskiy prospect 4, 119991, Moscow, Russia
| | - Madison Turk
- Department of Microbiology, Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3330 Hospital Drive N.W, Calgary, Alberta, T2N 4N1, Canada
| | - Craig N Jenne
- Department of Microbiology, Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3330 Hospital Drive N.W, Calgary, Alberta, T2N 4N1, Canada. .,Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, HRIC 2C26, 3280 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada.
| | - Seok-Joo Kim
- Department of Microbiology, Immunology and Infectious Diseases, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, HRIC 3330 Hospital Drive N.W, Calgary, Alberta, T2N 4N1, Canada. .,Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, HRIC 4C49, 3280 Hospital Drive N.W., Calgary, Alberta, T2N 4N1, Canada.
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Type I Interferon Signaling to Dendritic Cells Limits Murid Herpesvirus 4 Spread from the Olfactory Epithelium. J Virol 2017; 91:JVI.00951-17. [PMID: 28904198 DOI: 10.1128/jvi.00951-17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/08/2017] [Indexed: 12/23/2022] Open
Abstract
Murid herpesvirus 4 (MuHV-4) is a B cell-tropic gammaherpesvirus that can be studied in vivo Despite viral evasion, type I interferons (IFN-I) limit its spread. After MuHV-4 inoculation into footpads, IFN-I protect lymph node subcapsular sinus macrophages (SSM) against productive infection; after peritoneal inoculation, they protect splenic marginal zone macrophages, and they limit MuHV-4 replication in the lungs. While invasive infections can be used to test specific aspects of host colonization, it is also important to understand natural infection. MuHV-4 taken up spontaneously by alert mice enters them via olfactory neurons. We determined how IFN-I act in this context. Blocking IFN-I signaling did not increase neuronal infection but allowed the virus to spread to the adjacent respiratory epithelium. In lymph nodes, a complete IFN-I signaling block increased MuHV-4 lytic infection in SSM and increased the number of dendritic cells (DC) expressing viral green fluorescent protein (GFP) independently of lytic infection. A CD11c+ cell-directed signaling block increased infection of DC only. However, this was sufficient to increase downstream infection, consistent with DC providing the main viral route to B cells. The capacity of IFN-I to limit DC infection indicated that viral IFN-I evasion was only partly effective. Therefore, DC are a possible target for IFN-I-based interventions to reduce host colonization.IMPORTANCE Human gammaherpesviruses infect B cells and cause B cell cancers. Interventions to block virus binding to B cells have not stopped their infection. Therefore, we must identify other control points that are relevant to natural infection. Human infections are difficult to analyze. However, gammaherpesviruses colonize all mammals. A related gammaherpesvirus of mice reaches B cells not directly but via infected dendritic cells. We show that type I interferons, an important general antiviral defense, limit gammaherpesvirus B cell infection by acting on dendritic cells. Therefore, dendritic cell infection is a potential point of interferon-based therapeutic intervention.
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HIV Fusion in Dendritic Cells Occurs Mainly at the Surface and Is Limited by Low CD4 Levels. J Virol 2017; 91:JVI.01248-17. [PMID: 28814521 DOI: 10.1128/jvi.01248-17] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/10/2017] [Indexed: 01/06/2023] Open
Abstract
HIV-1 poorly infects monocyte-derived dendritic cells (MDDCs). This is in large part due to SAMHD1, which restricts viral reverse transcription. Pseudotyping HIV-1 with vesicular stomatitis virus G protein (VSV-G) strongly enhances infection, suggesting that earlier steps of viral replication, including fusion, are also inefficient in MDDCs. The site of HIV-1 fusion remains controversial and may depend on the cell type, with reports indicating that it occurs at the plasma membrane or, conversely, in an endocytic compartment. Here, we examined the pathways of HIV-1 entry in MDDCs. Using a combination of temperature shift and fusion inhibitors, we show that HIV-1 fusion mainly occurs at the cell surface. We then asked whether surface levels or intracellular localization of CD4 modulates HIV-1 entry. Increasing CD4 levels strongly enhanced fusion and infection with various HIV-1 isolates, including reference and transmitted/founder strains, but not with BaL, which uses low CD4 levels for entry. Overexpressing coreceptors did not facilitate viral infection. To further study the localization of fusion events, we generated CD4 mutants carrying heterologous cytoplasmic tails (LAMP1 or Toll-like receptor 7 [TLR7]) to redirect the molecule to intracellular compartments. The intracellular CD4 mutants did not facilitate HIV-1 fusion and replication in MDDCs. Fusion of an HIV-2 isolate with MDDCs was also enhanced by increasing surface CD4 levels. Our results demonstrate that MDDCs are inefficiently infected by various HIV-1 and HIV-2 strains, in part because of low CD4 levels. In these cells, viral fusion occurs mainly at the surface, and probably not after internalization.IMPORTANCE Dendritic cells (DCs) are professional antigen-presenting cells inducing innate and adaptive immune responses. DCs express the HIV receptor CD4 and are potential target cells for HIV. There is debate about the sensitivity of DCs to productive HIV-1 and HIV-2 infection. The fusion step of the viral replication cycle is inefficient in DCs, and the underlying mechanisms are poorly characterized. We show that increasing the levels of CD4 at the plasma membrane allows more HIV fusion and productive infection in DCs. We further demonstrate that HIV fusion occurs mainly at the cell surface and not in an intracellular compartment. Our results help us understand why DCs are poorly sensitive to HIV infection.
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Jakobsdottir GM, Iliopoulou M, Nolan R, Alvarez L, Compton AA, Padilla-Parra S. On the Whereabouts of HIV-1 Cellular Entry and Its Fusion Ports. Trends Mol Med 2017; 23:932-944. [PMID: 28899754 DOI: 10.1016/j.molmed.2017.08.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 08/12/2017] [Accepted: 08/14/2017] [Indexed: 01/06/2023]
Abstract
HIV-1 disseminates to diverse tissues through different cell types and establishes long-lived reservoirs. The exact cellular compartment where fusion occurs differs depending on the cell type and mode of viral transmission. This implies that HIV-1 may modulate a number of common host cell factors in different cell types. In this review, we evaluate recent advances on the host cell factors that play an important role in HIV-1 entry and fusion. New insights from restriction factors inhibiting virus-cell fusion in vitro may contribute to the development of future therapeutic interventions. Collectively, novel findings underline the need for potent, host-directed therapies that disrupt the earliest stages of the virus life cycle and preclude the emergence of resistant viral variants.
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Affiliation(s)
- G Maria Jakobsdottir
- Wellcome Trust Centre for Human Genetics, Cellular Imaging, University of Oxford, Oxford, UK
| | - Maro Iliopoulou
- Wellcome Trust Centre for Human Genetics, Cellular Imaging, University of Oxford, Oxford, UK
| | - Rory Nolan
- Wellcome Trust Centre for Human Genetics, Cellular Imaging, University of Oxford, Oxford, UK
| | - Luis Alvarez
- Wellcome Trust Centre for Human Genetics, Cellular Imaging, University of Oxford, Oxford, UK
| | - Alex A Compton
- HIV Dynamics and Replication Program, National Cancer Institute, Frederick, MD 21702, USA
| | - Sergi Padilla-Parra
- Wellcome Trust Centre for Human Genetics, Cellular Imaging, University of Oxford, Oxford, UK; Division of Structural Biology, University of Oxford,The Henry Wellcome Building for Genomic Medicine, Headington, Oxford OX3 7BN, UK.
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Different Expression of Interferon-Stimulated Genes in Response to HIV-1 Infection in Dendritic Cells Based on Their Maturation State. J Virol 2017; 91:JVI.01379-16. [PMID: 28148784 DOI: 10.1128/jvi.01379-16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 01/20/2017] [Indexed: 11/20/2022] Open
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells whose functions are dependent on their degree of differentiation. In their immature state, DCs capture pathogens and migrate to the lymph nodes. During this process, DCs become resident mature cells specialized in antigen presentation. DCs are characterized by a highly limiting environment for human immunodeficiency virus type 1 (HIV-1) replication due to the expression of restriction factors such as SAMHD1 and APOBEC3G. However, uninfected DCs capture and transfer viral particles to CD4 lymphocytes through a trans-enhancement mechanism in which chemokines are involved. We analyzed changes in gene expression with whole-genome microarrays when immature DCs (IDCs) or mature DCs (MDCs) were productively infected using Vpx-loaded HIV-1 particles. Whereas productive HIV infection of IDCs induced expression of interferon-stimulated genes (ISGs), such induction was not produced in MDCs, in which a sharp decrease in ISG- and CXCR3-binding chemokines was observed, lessening trans-infection of CD4 lymphocytes. Similar patterns of gene expression were found when DCs were infected with HIV-2 that naturally expresses Vpx. Differences were also observed under conditions of restrictive HIV-1 infection, in the absence of Vpx. ISG expression was not modified in IDCs, whereas an increase of ISG- and CXCR3-binding chemokines was observed in MDCs. Overall these results suggest that sensing and restriction of HIV-1 infection are different in IDCs and MDCs. We propose that restrictive infection results in increased virulence through different mechanisms. In IDCs avoidance of sensing and induction of ISGs, whereas in MDCs increased production of CXCR3-binding chemokines, would result in lymphocyte attraction and enhanced infection at the immune synapse.IMPORTANCE In this work we describe for the first time the activation of a different genetic program during HIV-1 infection depending on the state of maturation of DCs. This represents a breakthrough in the understanding of the restriction to HIV-1 infection of DCs. The results show that infection of DCs by HIV-1 reprograms their gene expression pattern. In immature cells, productive HIV-1 infection activates interferon-related genes involved in the control of viral replication, thus inducing an antiviral state in surrounding cells. Paradoxically, restriction of HIV-1 by SAMHD1 would result in lack of sensing and IFN activation, thus favoring initial HIV-1 escape from the innate immune response. In mature DCs, restrictive infection results in HIV-1 sensing and induction of ISGs, in particular CXCR3-binding chemokines, which could favor the transmission of HIV to lymphocytes. Our data support the hypothesis that genetic DC reprograming by HIV-1 infection favors viral escape and dissemination, thus increasing HIV-1 virulence.
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Prasad A, Kulkarni R, Jiang S, Groopman JE. Cocaine Enhances DC to T-cell HIV-1 Transmission by Activating DC-SIGN/LARG/LSP1 Complex and Facilitating Infectious Synapse Formation. Sci Rep 2017; 7:40648. [PMID: 28094782 PMCID: PMC5240552 DOI: 10.1038/srep40648] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
DC-SIGN is a dendritic cell surface structure which participates in binding and transmission of HIV-1. Here, for the first time we demonstrate that cocaine induces over expression of DC-SIGN and significantly enhances virus transfer from DCs to T-cells by increasing the binding and internalization of HIV-1 in DCs. We found that cocaine activates a DC-SIGN mediated 'signalosome' complex by enhancing its association with LARG and LSP1. Further, LARG was observed to participate in DC-SIGN mediated internalization of HIV-1 in DCs. Intracellular trafficking studies of HIV-1 in cocaine treated DCs revealed increased co-localization of HIV-1 with endosomal or multi vesicular body (MVB) markers such as CD81 and VPS4 and decreased co-localization with the phagolysomal marker LAMP1; this signified altered intracellular trafficking and decreased degradation of HIV-1 in cocaine treated DCs. Furthermore, we found that cocaine induced activation of LARG which in turn activated Rho A and the focal adhesion molecules FAK, Pyk2 and paxillin. This signaling cascade enhanced the formation of an infectious synapse between DCs and T-cells. Our study provides insight into the molecular mechanisms of cocaine's contribution to key components in HIV pathogenesis and highlights novel targets for interrupting the virus life cycle in substance using hosts.
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Affiliation(s)
- Anil Prasad
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Rutuja Kulkarni
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Shuxian Jiang
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Jerome E. Groopman
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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Presti R, Pantaleo G. The Immunopathogenesis of HIV-1 Infection. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00092-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Aravantinou M, Frank I, Hallor M, Singer R, Tharinger H, Kenney J, Gettie A, Grasperge B, Blanchard J, Salazar A, Piatak M, Lifson JD, Robbiani M, Derby N. PolyICLC Exerts Pro- and Anti-HIV Effects on the DC-T Cell Milieu In Vitro and In Vivo. PLoS One 2016; 11:e0161730. [PMID: 27603520 PMCID: PMC5014349 DOI: 10.1371/journal.pone.0161730] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Accepted: 07/14/2016] [Indexed: 12/24/2022] Open
Abstract
Myeloid dendritic cells (mDCs) contribute to both HIV pathogenesis and elicitation of antiviral immunity. Understanding how mDC responses to stimuli shape HIV infection outcomes will inform HIV prevention and treatment strategies. The long double-stranded RNA (dsRNA) viral mimic, polyinosinic polycytidylic acid (polyIC, PIC) potently stimulates DCs to focus Th1 responses, triggers direct antiviral activity in vitro, and boosts anti-HIV responses in vivo. Stabilized polyICLC (PICLC) is being developed for vaccine adjuvant applications in humans, making it critical to understand how mDC sensing of PICLC influences HIV infection. Using the monocyte-derived DC (moDC) model, we sought to describe how PICLC (vs. other dsRNAs) impacts HIV infection within DCs and DC-T cell mixtures. We extended this work to in vivo macaque rectal transmission studies by administering PICLC with or before rectal SIVmac239 (SIVwt) or SIVmac239ΔNef (SIVΔNef) challenge. Like PIC, PICLC activated DCs and T cells, increased expression of α4β7 and CD169, and induced type I IFN responses in vitro. The type of dsRNA and timing of dsRNA exposure differentially impacted in vitro DC-driven HIV infection. Rectal PICLC treatment similarly induced DC and T cell activation and pro- and anti-HIV factors locally and systemically. Importantly, this did not enhance SIV transmission in vivo. Instead, SIV acquisition was marginally reduced after a single high dose challenge. Interestingly, in the PICLC-treated, SIVΔNef-infected animals, SIVΔNef viremia was higher, in line with the importance of DC and T cell activation in SIVΔNef replication. In the right combination anti-HIV strategy, PICLC has the potential to limit HIV infection and boost HIV immunity.
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Affiliation(s)
- Meropi Aravantinou
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Ines Frank
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Magnus Hallor
- Center for Biomedical Research, Population Council, New York, NY, United States of America
- Linköping University, Linköping, Sweden
| | - Rachel Singer
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Hugo Tharinger
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Jessica Kenney
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Agegnehu Gettie
- Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY, United States of America
| | - Brooke Grasperge
- Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA, United States of America
| | - James Blanchard
- Tulane National Primate Research Center, Tulane University Health Sciences Center, Covington, LA, United States of America
| | | | - Michael Piatak
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD, United States of America
| | - Jeffrey D. Lifson
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, MD, United States of America
| | - Melissa Robbiani
- Center for Biomedical Research, Population Council, New York, NY, United States of America
| | - Nina Derby
- Center for Biomedical Research, Population Council, New York, NY, United States of America
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Abstract
Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever.
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Affiliation(s)
- Monique R Anderson
- National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Viral Immunology Section, Bethesda, MD, 20892, USA.
- Department of Pathology Molecular and Cellular Basis of Disease Graduate Program, University of Virginia School of Medicine, Charlottesville, VA, 22903, USA.
| | - Fatah Kashanchi
- George Mason University, National Center for Biodefense and Infectious Disease, Laboratory of Molecular Virology, Manassas, VA, 20110, USA
| | - Steven Jacobson
- National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuroimmunology Branch, Viral Immunology Section, Bethesda, MD, 20892, USA
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Czubala MA, Finsterbusch K, Ivory MO, Mitchell JP, Ahmed Z, Shimauchi T, Karoo ROS, Coulman SA, Gateley C, Birchall JC, Blanchet FP, Piguet V. TGFβ Induces a SAMHD1-Independent Post-Entry Restriction to HIV-1 Infection of Human Epithelial Langerhans Cells. J Invest Dermatol 2016; 136:1981-1989. [PMID: 27375111 DOI: 10.1016/j.jid.2016.05.123] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/13/2016] [Accepted: 05/31/2016] [Indexed: 11/24/2022]
Abstract
Sterile alpha motif (SAM) and histidine-aspartic (HD) domains protein 1 (SAMHD1) was previously identified as a critical post-entry restriction factor to HIV-1 infection in myeloid dendritic cells. Here we show that SAMHD1 is also expressed in epidermis-isolated Langerhans cells (LC), but degradation of SAMHD1 does not rescue HIV-1 or vesicular stomatitis virus G-pseudotyped lentivectors infection in LC. Strikingly, using Langerhans cells model systems (mutz-3-derived LC, monocyte-derived LC [MDLC], and freshly isolated epidermal LC), we characterize previously unreported post-entry restriction activity to HIV-1 in these cells, which acts at HIV-1 reverse transcription, but remains independent of restriction factors SAMHD1 and myxovirus resistance 2 (MX2). We demonstrate that transforming growth factor-β signaling confers this potent HIV-1 restriction in MDLC during their differentiation and blocking of mothers against decapentaplegic homolog 2 (SMAD2) signaling in MDLC restores cells' infectivity. Interestingly, maturation of MDLC with a toll-like receptor 2 agonist or transforming growth factor-α significantly increases cells' susceptibility to HIV-1 infection, which may explain why HIV-1 acquisition is increased during coinfection with sexually transmitted infections. In conclusion, we report a SAMHD1-independent post-entry restriction in MDLC and LC isolated from epidermis, which inhibits HIV-1 replication. A better understanding of HIV-1 restriction and propagation from LC to CD4(+) T cells may help in the development of new microbicides or vaccines to curb HIV-1 infection at its earliest stages during mucosal transmission.
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Affiliation(s)
- Magdalena A Czubala
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Katja Finsterbusch
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Matthew O Ivory
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK
| | - J Paul Mitchell
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Zahra Ahmed
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Takatoshi Shimauchi
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | | | - Sion A Coulman
- Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK
| | - Christopher Gateley
- Aneurin Bevan University Health Board Royal Gwent Hospital, Newport NP20 2UB, UK
| | - James C Birchall
- Cardiff University School of Pharmacy and Pharmaceutical Sciences, Cardiff CF10 3NB, UK
| | - Fabien P Blanchet
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Vincent Piguet
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
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Wheeler LA, Trifonova RT, Vrbanac V, Barteneva NS, Liu X, Bollman B, Onofrey L, Mulik S, Ranjbar S, Luster AD, Tager AM, Lieberman J. TREX1 Knockdown Induces an Interferon Response to HIV that Delays Viral Infection in Humanized Mice. Cell Rep 2016; 15:1715-27. [PMID: 27184854 DOI: 10.1016/j.celrep.2016.04.048] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 03/21/2016] [Accepted: 04/09/2016] [Indexed: 10/21/2022] Open
Abstract
Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection. In humanized mice, even though TREX1 knockdown increased infiltrating immune cells, it delayed viral replication for 3-4 weeks. Similarly intravaginal application of type I interferons the day before HIV infection induced interferon responsive genes, reduced inflammation, and decreased viral replication. However, intravenous interferon enhanced inflammation and infection. Thus, in models of human sexual transmission, a localized interferon response inhibits HIV transmission but systemic interferons do not.
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Affiliation(s)
- Lee Adam Wheeler
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA
| | - Radiana T Trifonova
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Vladimir Vrbanac
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA
| | - Natasha S Barteneva
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Xing Liu
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Brooke Bollman
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Lauren Onofrey
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Sachin Mulik
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Shahin Ranjbar
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
| | - Andrew D Luster
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA
| | - Andrew M Tager
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02139, USA
| | - Judy Lieberman
- Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
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Oliva H, Pacheco R, Martinez-Navio JM, Rodríguez-García M, Naranjo-Gómez M, Climent N, Prado C, Gil C, Plana M, García F, Miró JM, Franco R, Borras FE, Navaratnam N, Gatell JM, Gallart T. Increased expression with differential subcellular location of cytidine deaminase APOBEC3G in human CD4(+) T-cell activation and dendritic cell maturation. Immunol Cell Biol 2016; 94:689-700. [PMID: 26987686 DOI: 10.1038/icb.2016.28] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2015] [Revised: 03/09/2016] [Accepted: 03/13/2016] [Indexed: 01/04/2023]
Abstract
APOBEC3G (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G; A3G) is an innate defense protein showing activity against retroviruses and retrotransposons. Activated CD4(+) T cells are highly permissive for HIV-1 replication, whereas resting CD4(+) T cells are refractory. Dendritic cells (DCs), especially mature DCs, are also refractory. We investigated whether these differences could be related to a differential A3G expression and/or subcellular distribution. We found that A3G mRNA and protein expression is very low in resting CD4(+) T cells and immature DCs, but increases strongly following T-cell activation and DC maturation. The Apo-7 anti-A3G monoclonal antibody (mAb), which was specifically developed, confirmed these differences at the protein level and disclosed that A3G is mainly cytoplasmic in resting CD4(+) T cells and immature DCs. Nevertheless, A3G translocates to the nucleus in activated-proliferating CD4(+) T cells, yet remaining cytoplasmic in matured DCs, a finding confirmed by immunoblotting analysis of cytoplasmic and nuclear fractions. Apo-7 mAb was able to immunoprecipitate endogenous A3G allowing to detect complexes with numerous proteins in activated-proliferating but not in resting CD4(+) T cells. The results show for the first time the nuclear translocation of A3G in activated-proliferating CD4(+) T cells.
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Affiliation(s)
- Harold Oliva
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Rodrigo Pacheco
- Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andres Bello, Santiago, Chile.,Laboratorio de Neuroinmunología, Fundación Ciencia and Vida, Santiago, Chile
| | - José M Martinez-Navio
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain
| | - Marta Rodríguez-García
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Service of Immunology, Hospital Clínic Universitari de Barcelona, Barcelona, Spain
| | - Mar Naranjo-Gómez
- LIRAD (Laboratory of Immunobiology for Research and Diagnostic Applications), Institut d'Investigació Germans Trias-Pujol, Autonomous University of Barcelona, Badalona (Barcelona), Spain
| | - Núria Climent
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Carolina Prado
- Laboratorio de Neuroinmunología, Fundación Ciencia and Vida, Santiago, Chile
| | - Cristina Gil
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Montserrat Plana
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Felipe García
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - José M Miró
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Rafael Franco
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.,CIBERNED Centro de Investigación en Red, Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain
| | - Francesc E Borras
- IVECAT-Group, Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain.,Nephrology Service, Germans Trias i Pujol University Hospital, Badalona, Spain
| | - Naveenan Navaratnam
- MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, London, UK
| | - José M Gatell
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Service of Infectious Diseases and AIDS Unit, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Teresa Gallart
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-AIDS Research Group and HIV Vaccine Development in Catalonia (HIVACAT), Hospital Clínic de Barcelona, Faculty of Medicine, University of Barcelona, Barcelona, Spain.,Service of Immunology, Hospital Clínic Universitari de Barcelona, Barcelona, Spain
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Zaccard CR, Rinaldo CR, Mailliard RB. Linked in: immunologic membrane nanotube networks. J Leukoc Biol 2016; 100:81-94. [PMID: 26931578 DOI: 10.1189/jlb.4vmr0915-395r] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 02/01/2016] [Indexed: 01/01/2023] Open
Abstract
Membrane nanotubes, also termed tunneling nanotubes, are F-actin-based structures that can form direct cytoplasmic connections and support rapid communication between distant cells. These nanoscale conduits have been observed in diverse cell types, including immune, neuronal, stromal, cancer, and stem cells. Until recently, little was known about the mechanisms involved in membrane nanotube development in myeloid origin APCs or how membrane nanotube networks support their ability to bridge innate and adaptive immunity. New research has provided insight into the modes of induction and regulation of the immune process of "reticulation" or the development of multicellular membrane nanotube networks in dendritic cells. Preprogramming by acute type 1 inflammatory mediators at their immature stage licenses mature type 1-polarized dendritic cells to reticulate upon subsequent interaction with CD40 ligand-expressing CD4(+) Th cells. Dendritic cell reticulation can support direct antigen transfer for amplification of specific T cell responses and can be positively or negatively regulated by signals from distinct Th cell subsets. Membrane nanotubes not only enhance the ability of immature dendritic cells to sense pathogens and rapidly mobilize nearby antigen-presenting cells in the peripheral tissues but also likely support communication of pathogen-related information from mature migratory dendritic cells to resident dendritic cells in lymph nodes. Therefore, the reticulation process facilitates a coordinated multicellular response for the efficient initiation of cell-mediated adaptive immune responses. Herein, we discuss studies focused on the molecular mechanisms of membrane nanotube formation, structure, and function in the context of immunity and how pathogens, such as HIV-1, may use dendritic cell reticulation to circumvent host defenses.
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Affiliation(s)
- C R Zaccard
- Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania, USA and
| | - C R Rinaldo
- Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania, USA and Department of Pathology, University of Pittsburgh, Pennsylvania, USA
| | - R B Mailliard
- Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pennsylvania, USA and
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Caucheteux SM, Mitchell JP, Ivory MO, Hirosue S, Hakobyan S, Dolton G, Ladell K, Miners K, Price DA, Kan-Mitchell J, Sewell AK, Nestle F, Moris A, Karoo RO, Birchall JC, Swartz MA, Hubbel JA, Blanchet FP, Piguet V. Polypropylene Sulfide Nanoparticle p24 Vaccine Promotes Dendritic Cell-Mediated Specific Immune Responses against HIV-1. J Invest Dermatol 2016; 136:1172-1181. [PMID: 26896775 DOI: 10.1016/j.jid.2016.01.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 12/24/2022]
Abstract
Delivery of vaccine formulations into the dermis using antigen-coated microneedle patches is a promising and safe approach because of efficient antigen delivery and safety. We evaluated an intradermal vaccine using HIV-1 p24 Gag peptide-conjugated polypropylene sulfide nanoparticles to induce immunity against HIV-1. This peptide-conjugated polypropylene sulfide nanoparticle formulation did not accelerate the maturation of blood- or skin-derived subsets of dendritic cells, either generated in vitro or purified ex vivo, despite efficient uptake in the absence of adjuvant. Moreover, dendritic cell-mediated capture of particulate antigen in this form induced potent HIV-1-specific CD4(+) T-cell responses, as well as B-cell-mediated antibody production. Nanoparticle-based intradermal antigen delivery may therefore provide a new option in the global effort to develop an effective vaccine against HIV-1.
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Affiliation(s)
- Stephan M Caucheteux
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - John P Mitchell
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Matthew O Ivory
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK; School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Sachiko Hirosue
- Institute of Bioengineering, School of Life Sciences and School of Engineering, Lausanne, Switzerland
| | - Svetlana Hakobyan
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Garry Dolton
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Kristin Ladell
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Kelly Miners
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - David A Price
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - June Kan-Mitchell
- Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA
| | - Andrew K Sewell
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Frank Nestle
- St. John's Institute of Dermatology, King's College London, London, UK
| | - Arnaud Moris
- Sorbonne Universités, UPMC Paris 06, INSERM U1135, CNRS ERL 8255, Center for Immunology and Microbial Infections, F-75013, Paris, France
| | | | - James C Birchall
- School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, UK
| | - Melody A Swartz
- Institute of Bioengineering, School of Life Sciences and School of Engineering, Lausanne, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois, USA
| | - Jeffrey A Hubbel
- Institute of Bioengineering, School of Life Sciences and School of Engineering, Lausanne, Switzerland; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois, USA
| | - Fabien P Blanchet
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Vincent Piguet
- Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
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38
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Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans-Infection of CD4+ T Cells. J Virol 2015; 90:2928-37. [PMID: 26719250 DOI: 10.1128/jvi.03008-15] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Accepted: 12/21/2015] [Indexed: 12/31/2022] Open
Abstract
UNLABELLED The gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4(+) T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viral trans-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection. IMPORTANCE In this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1 trans-infection of CD4(+) T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.
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Su B, Peressin M, Ducloy C, Penichon J, Mayr LM, Laumond G, Schmidt S, Decoville T, Moog C. Short Communication: Exploring Antibody Potential as Prophylactic/Therapeutic Strategies for Prevention of Early Mucosal HIV-1 Infection. AIDS Res Hum Retroviruses 2015; 31:1187-91. [PMID: 26252799 DOI: 10.1089/aid.2015.0041] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Mucosal tissues are the predominant sites for genital HIV-1 transmission. We investigated the mechanisms by which broadly neutralizing antibodies (bNAbs) inhibit HIV-1 replication in a coculture model including primary mucosal dendritic cells (DCs), such as Langerhans cells, interstitial dendritic cells, and CD4(+) T lymphocytes. We show that bNAbs efficiently prevent HIV-1 infection by inhibiting HIV-1 transmission to CD4(+) T lymphocytes. This inhibition of cell-to-cell transmission was observed with equal potency as the inhibition of cell-free infection of primary CD4(+) T lymphocytes. In addition, a decrease in HIV-1 replication in DCs and the induction of DC maturation were detected. This additional inhibition was Fc mediated as it was blocked by the use of specific anti-FcγR monoclonal Abs. The DC maturation by bNAbs during HIV transmission may contribute to mucosal protection. Therefore, multiple antibody-mediated inhibitory functions should be combined for the improvement of future preventive/therapeutic strategies to cure HIV.
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Affiliation(s)
- Bin Su
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Maryse Peressin
- Centre d'investigation clinique/Service de neurologie, INSERM CIC-P1434, Hôpital de Hautepierre, Strasbourg, France
| | - Camille Ducloy
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Julien Penichon
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Luzia M. Mayr
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Géraldine Laumond
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Sylvie Schmidt
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
| | - Thomas Decoville
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Vaccine Research Institute, Hôpital Henri Mondor, Créteil, France
| | - Christiane Moog
- INSERM UMR S_1109, Centre de Recherche en Immunologie et Hématologie, Faculté de Médecine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France
- Vaccine Research Institute, Hôpital Henri Mondor, Créteil, France
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Chauhan S, Ahmed Z, Bradfute SB, Arko-Mensah J, Mandell MA, Won Choi S, Kimura T, Blanchet F, Waller A, Mudd MH, Jiang S, Sklar L, Timmins GS, Maphis N, Bhaskar K, Piguet V, Deretic V. Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential. Nat Commun 2015; 6:8620. [PMID: 26503418 PMCID: PMC4624223 DOI: 10.1038/ncomms9620] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2015] [Accepted: 09/11/2015] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a conserved homeostatic process active in all human cells and affecting a spectrum of diseases. Here we use a pharmaceutical screen to discover new mechanisms for activation of autophagy. We identify a subset of pharmaceuticals inducing autophagic flux with effects in diverse cellular systems modelling specific stages of several human diseases such as HIV transmission and hyperphosphorylated tau accumulation in Alzheimer's disease. One drug, flubendazole, is a potent inducer of autophagy initiation and flux by affecting acetylated and dynamic microtubules in a reciprocal way. Disruption of dynamic microtubules by flubendazole results in mTOR deactivation and dissociation from lysosomes leading to TFEB (transcription factor EB) nuclear translocation and activation of autophagy. By inducing microtubule acetylation, flubendazole activates JNK1 leading to Bcl-2 phosphorylation, causing release of Beclin1 from Bcl-2-Beclin1 complexes for autophagy induction, thus uncovering a new approach to inducing autophagic flux that may be applicable in disease treatment. Autophagy is a homeostatic process that could be a potential drug target in the treatment of disease. Here the authors identify in a pharmaceutical screen flubendazole as an inducer of autophagy initiation and flux by affecting microtubules, mTOR, TFEB and Beclin 1 activity.
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Affiliation(s)
- Santosh Chauhan
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Zahra Ahmed
- Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK
| | - Steven B Bradfute
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - John Arko-Mensah
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Michael A Mandell
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Seong Won Choi
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Tomonori Kimura
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Fabien Blanchet
- Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK
| | - Anna Waller
- Department of Pathology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Michal H Mudd
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Shanya Jiang
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Larry Sklar
- Department of Pathology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Graham S Timmins
- College of Pharmacy, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Nicole Maphis
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Kiran Bhaskar
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.,Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
| | - Vincent Piguet
- Cardiff Institute of Infection &Immunity, Cardiff University, School of Medicine, Henry Wellcome Building, Heath Park CF14 4XN, Cardiff, UK
| | - Vojo Deretic
- Department of Molecular Genetics and Microbiology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA.,Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud, NE, Albuquerque, New Mexico 87131, USA
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Nguyen XN, Barateau V, Wu N, Berger G, Cimarelli A. The Frequency of Cytidine Editing of Viral DNA Is Differentially Influenced by Vpx and Nucleosides during HIV-1 or SIVMAC Infection of Dendritic Cells. PLoS One 2015; 10:e0140561. [PMID: 26496699 PMCID: PMC4619667 DOI: 10.1371/journal.pone.0140561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/28/2015] [Indexed: 01/02/2023] Open
Abstract
Two cellular factors are currently known to modulate lentiviral infection specifically in myeloid cells: SAMHD1 and APOBEC3A (A3A). SAMHD1 is a deoxynucleoside triphosphohydrolase that interferes with viral infection mostly by limiting the intracellular concentrations of dNTPs, while A3A is a cytidine deaminase that has been described to edit incoming vDNA. The restrictive phenotype of myeloid cells can be alleviated through the direct degradation of SAMHD1 by the HIV-2/SIVSM Vpx protein or else, at least in the case of HIV-1, by the exogenous supplementation of nucleosides that artificially overcome the catabolic activity of SAMHD1 on dNTPs. Here, we have used Vpx and dNs to explore the relationship existing between vDNA cytidine deamination and SAMHD1 during HIV-1 or SIVMAC infection of primary dendritic cells. Our results reveal an interesting inverse correlation between conditions that promote efficient infection of DCs and the extent of vDNA editing that may reflect the different susceptibility of vDNA to cytoplasmic effectors during the infection of myeloid cells.
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Affiliation(s)
- Xuan-Nhi Nguyen
- CIRI, Centre International de Recherche en Infectiologie, Lyon, F69364, France
- INSERM, U1111, 46 Allée d’Italie, Lyon, F69364, France
- Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, Lyon, F69364, France
- CNRS, UMR5308, 46 Allée d’Italie, Lyon, F69364, France
- University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon, F69364, France
| | - Véronique Barateau
- CIRI, Centre International de Recherche en Infectiologie, Lyon, F69364, France
- INSERM, U1111, 46 Allée d’Italie, Lyon, F69364, France
- Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, Lyon, F69364, France
- CNRS, UMR5308, 46 Allée d’Italie, Lyon, F69364, France
- University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon, F69364, France
| | - Nannan Wu
- CIRI, Centre International de Recherche en Infectiologie, Lyon, F69364, France
- INSERM, U1111, 46 Allée d’Italie, Lyon, F69364, France
- Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, Lyon, F69364, France
- CNRS, UMR5308, 46 Allée d’Italie, Lyon, F69364, France
- University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon, F69364, France
- Institute of BioMedical Science (IBMS), East China Normal University (ECNU), Shanghai, China
| | - Gregory Berger
- CIRI, Centre International de Recherche en Infectiologie, Lyon, F69364, France
- INSERM, U1111, 46 Allée d’Italie, Lyon, F69364, France
- Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, Lyon, F69364, France
- CNRS, UMR5308, 46 Allée d’Italie, Lyon, F69364, France
- University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon, F69364, France
| | - Andrea Cimarelli
- CIRI, Centre International de Recherche en Infectiologie, Lyon, F69364, France
- INSERM, U1111, 46 Allée d’Italie, Lyon, F69364, France
- Ecole Normale Supérieure de Lyon, 46 Allée d’Italie, Lyon, F69364, France
- CNRS, UMR5308, 46 Allée d’Italie, Lyon, F69364, France
- University of Lyon, Lyon I, UMS3444/US8 BioSciences Gerland, Lyon, F69364, France
- * E-mail:
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42
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Sachdeva M, Sharma A, Arora SK. Functional Impairment of Myeloid Dendritic Cells during Advanced Stage of HIV-1 Infection: Role of Factors Regulating Cytokine Signaling. PLoS One 2015; 10:e0140852. [PMID: 26492336 PMCID: PMC4619614 DOI: 10.1371/journal.pone.0140852] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 10/01/2015] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION Severely immunocompromised state during advanced stage of HIV-1 infection has been linked to functionally defective antigen presentation by dendritic cells (DCs). The molecular mechanisms behind DC impairment are still obscure. We investigated changes in DC function and association of key regulators of cytokine signaling during different stages of HIV-1 infection and following antiretroviral therapy (ART). METHODS Phenotypic and functional characteristics of circulating myeloid DCs (mDCs) in 56 ART-naive patients (23 in early and 33 in advanced stage of disease), 36 on ART and 24 healthy controls were evaluated. Sixteen patients were studied longitudinally prior-to and 6 months after the start of ART. For functional studies, monocyte-derived DCs (Mo-DCs) were evaluated for endocytosis, allo-stimulation and cytokine secretion. The expression of suppressor of cytokine signaling (SOCS)-1 and other regulators of cytokine signaling was evaluated by real-time RT-PCR. RESULTS The ability to respond to an antigenic stimulation was severely impaired in patients in advanced HIV-1 disease which showed partial recovery in the treated group. Mo-DCs from patients with advanced HIV-disease remained immature with low allo-stimulation and reduced cytokine secretion even after TLR-4 mediated stimulation ex-vivo. The cells had an increased expression of negative regulatory factors like SOCS-1, SOCS-3, SH2-containing phosphatase (SHP)-1 and a reduced expression of positive regulators like Janus kinase (JAK)2 and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)1. A functional recovery after siRNA mediated silencing of SOCS-1 in these mo-DCs confirms the role of negative regulatory factors in functional impairment of these cells. CONCLUSIONS Functionally defective DCs in advanced stage of HIV-1 infection seems to be due to imbalanced state of negative and positive regulatory gene expression. Whether this is a cause or effect of increased viral replication at this stage of disease, needs further investigation. The information may be useful in design of novel therapeutic targets for better management of disease.
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Affiliation(s)
- Meenakshi Sachdeva
- Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Aman Sharma
- Department of Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Sunil K. Arora
- Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
- * E-mail:
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Magnus C, Reh L, Trkola A. HIV-1 resistance to neutralizing antibodies: Determination of antibody concentrations leading to escape mutant evolution. Virus Res 2015; 218:57-70. [PMID: 26494166 DOI: 10.1016/j.virusres.2015.10.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Revised: 10/07/2015] [Accepted: 10/07/2015] [Indexed: 11/15/2022]
Abstract
Broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) are considered vital components of novel therapeutics and blueprints for vaccine research. Yet escape to even the most potent of these antibodies is imminent in natural infection. Measures to define antibody efficacy and prevent mutant selection are thus urgently needed. Here, we derive a mathematical framework to predict the concentration ranges for which antibody escape variants can outcompete their viral ancestors, referred to as mutant selection window (MSW). When determining the MSW, we focus on the differential efficacy of neutralizing antibodies against HIV-1 in two canonical infection routes, free-virus infection and cell-cell transmission. The latter has proven highly effective in vitro suggesting its importance for both in vivo spread as well as for escaping targeted intervention strategies. We observed a range of MSW patterns that highlight the potential of mutants to arise in both transmission pathways and over wide concentration ranges. Most importantly, we found that only when the arising mutant has both, residual sensitivity to the neutralizing antibody and reduced infectivity compared to the parental virus, antibody dosing outside of the MSW to restrict mutant selection is possible. Emergence of mutants that provide complete escape and have no considerable fitness loss cannot be prevented by adjusting antibody doses. The latter may in part explain the ubiquitous resistance to neutralizing antibodies observed in natural infection and antibody treatment. Based on our findings, combinations of antibodies targeting different epitopes should be favored for antibody-based interventions as this may render complete resistance less likely to occur and also increase chances that multiple escapes result in severe fitness loss of the virus making longer-term antibody treatment more feasible.
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Affiliation(s)
- Carsten Magnus
- Institute of Medical Virology, University of Zurich, Switzerland; Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
| | - Lucia Reh
- Institute of Medical Virology, University of Zurich, Switzerland.
| | - Alexandra Trkola
- Institute of Medical Virology, University of Zurich, Switzerland.
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Abstract
HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. Studies of these HIV-1 variants provide critical information about the transmission bottlenecks and the selective pressures acting on the virus in the transmission fluid and in the recipient tissues. These studies reveal that T/F virus phenotypes are shaped by stochastic and selective forces that restrict transmission and may be targets for prevention strategies. In this Review, we highlight how studies of T/F viruses contribute to a better understanding of the biology of HIV-1 transmission and discuss how these findings affect HIV-1 prevention strategies.
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Human Blood-Circulating Basophils Capture HIV-1 and Mediate Viral trans-Infection of CD4+ T Cells. J Virol 2015; 89:8050-62. [PMID: 26018157 DOI: 10.1128/jvi.01021-15] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 05/18/2015] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Cell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Granulocytes are a category of white blood cells, comprising mainly basophils, neutrophils, and eosinophils, and participate in various inflammatory reactions and defense against pathogens. Here, we investigated the role of human blood granulocytes in the dissemination of HIV-1. These cells were found to express a variety of HIV-1 attachment factors (HAFs). Basophils expressed HAFs dendritic cell (DC)-specific intercellular adhesion molecule 3 (ICAM3)-grabbing nonintegrin (DC-SIGN), DC immunoreceptor (DCIR), heparan sulfate proteoglycan (HSPG), and α4β7 integrin and mediated the most efficient capture of HIV-1 on the cell surface. Neutrophils were found to express DCIR and demonstrated limited efficiency of viral capture. Eosinophils expressed α4β7 integrin but exhibited little or no virus-binding capacity. Intriguingly, following direct contact with CD4+ T cells, viruses harbored on the surface of basophils were transferred to T cells. The contact between basophils and CD4+ T cells and formation of infectious synapses appeared necessary for efficient HIV-1 spread. In HIV-1-infected individuals, the frequency of basophils remained fairly stable over the course of disease, regardless of CD4+ T depletion or the emergence of AIDS-associated opportunistic infections. Collectively, our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. Thus, strategies designed to prevent basophil-mediated viral capture and transfer may be developed into a new form of therapy. IMPORTANCE Cell-associated HIV-1 infection has been proposed to play a pivotal role in the spread of HIV-1 infection. Here, we demonstrated that human blood-circulating granulocytes, particularly basophils, can capture HIV-1 and mediate viral trans-infection of CD4+ T cells. The expression of a variety of HIV-1 attachment factors, such as the C-type lectins, etc., facilitates viral capture and transfer. Intriguingly, the frequency of basophils in patients with different levels of CD4+ T counts remains fairly stable during the course of disease. Our results provide novel insights into the roles of granulocytes, particularly basophils, in HIV-1 dissemination. We suggest that strategies designed to prevent basophil-mediated viral capture and transfer may be a new direction for the development of anti-HIV therapy.
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Kijewski SDG, Gummuluru S. A mechanistic overview of dendritic cell-mediated HIV-1 trans infection: the story so far. Future Virol 2015; 10:257-269. [PMID: 26213560 PMCID: PMC4508676 DOI: 10.2217/fvl.15.2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Despite progress in antiretroviral therapy, HIV-1 rebound after cessation of antiretroviral therapy suggests that establishment of long-term cellular reservoirs of virus is a significant barrier to functional cure. There is considerable evidence that dendritic cells (DCs) play an important role in systemic virus dissemination. Although productive infection of DCs is inefficient, DCs capture HIV-1 and transfer-captured particles to CD4+ T cells, a mechanism of DC-mediated HIV-1 trans infection. Recent findings suggest that DC-mediated trans infection of HIV-1 is dependent on recognition of GM3, a virus-particle-associated host-derived ligand, by CD169 expressed on DCs. In this review, we describe mechanisms of DC-mediated HIV-1 trans infection and discuss specifically the role of CD169 in establishing infection in CD4+ T cells.
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Affiliation(s)
- Suzanne DG Kijewski
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
| | - Suryaram Gummuluru
- Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA
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Frederico B, Chao B, May JS, Belz GT, Stevenson PG. A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread. Cell Host Microbe 2015; 15:457-70. [PMID: 24721574 DOI: 10.1016/j.chom.2014.03.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Revised: 12/05/2013] [Accepted: 02/03/2014] [Indexed: 12/12/2022]
Abstract
Gamma-herpesviruses (γHVs) are widespread oncogenic pathogens that chronically infect circulating lymphocytes. How they subvert the immune check-point function of the spleen to promote persistent infection is not clear. We show that Murid Herpesvirus-4 (MuHV-4) enters the spleen by infecting marginal zone (MZ) macrophages, which provided a conduit to MZ B cells. Relocation of MZ B cells to the white pulp allowed virus transfer to follicular dendritic cells. From here the virus reached germinal center B cells to establish persistent infection. Mice lacking MZ B cells, or treated with a sphingosine-1-phosphate receptor agonist to dislocate them, were protected against MuHV-4 colonization. MuHV-4 lacking ORF27, which encodes a glycoprotein necessary for efficient intercellular spread, could infect MZ macrophages but was impaired in long-term infection. Thus, MuHV-4, a γHV, exploits normal immune communication routes to spread by serial lymphoid/myeloid exchange.
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Affiliation(s)
- Bruno Frederico
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK
| | - Brittany Chao
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK
| | - Janet S May
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK
| | - Gabrielle T Belz
- Molecular Immunology, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3052, Australia
| | - Philip G Stevenson
- Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 2QQ, UK; Sir Albert Sakzewski Virus Research Centre and Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Queensland 4029, Australia.
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The role of human dendritic cells in HIV-1 infection. J Invest Dermatol 2014; 135:1225-1233. [PMID: 25407434 DOI: 10.1038/jid.2014.490] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 08/25/2014] [Accepted: 09/27/2014] [Indexed: 12/24/2022]
Abstract
Dendritic cells (DCs) and their subsets have multifaceted roles in the early stages of HIV-1 transmission and infection. DC studies have led to remarkable discoveries, including identification of restriction factors, cellular structures promoting viral transmission including the infectious synapse or the interplay of the C-type lectins, Langerin on Langerhans cells (LCs), and dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin on other DC subsets, limiting or facilitating HIV transmission to CD4(+) T cells, respectively. LCs/DCs are also exposed to encountering HIV-1 and other sexually transmitted infections (herpes simplex virus-2, bacteria, fungi), which reprogram HIV-1 interaction with these cells. This review will summarize advances in the role of DCs during HIV-1 infection and discuss their potential involvement in the development of preventive strategies against HIV-1 and other sexually transmitted infections.
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Shimauchi T, Piguet V. DC-T cell virological synapses and the skin: novel perspectives in dermatology. Exp Dermatol 2014; 24:1-4. [PMID: 25039899 DOI: 10.1111/exd.12511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/16/2014] [Indexed: 01/13/2023]
Abstract
Virological synapses (VS) increase cell-to-cell viral transmission and facilitate propagation of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukaemia virus type 1 (HTLV-1). VS formation also plays a more general role in viral replication and dissemination. VS have been observed in vitro and ex vivo between uninfected T cells and T cells infected with HIV-1 or HTLV-1. In addition, dendritic cells (DC) infected with HIV-1 also play an important role in viral transmission to uninfected CD4+ T cells via VS formation. Recent studies revealed that several DC subsets are also infected with HTLV-1. These findings may help explain the rapid dissemination of both viruses within secondary lymphoid tissues in vivo. VS also explain, at least in part, why HIV-1 can propagate in the mucosal sites during sexual transmission. Furthermore, in the case of HTLV-1, VS can potentially explain some of the features of HTLV-1-associated dermatitis as infected T cells in the skin contribute to the pathogenesis of this condition.
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Affiliation(s)
- Takatoshi Shimauchi
- Department of Dermatology and Academic Wound Healing, Institute of Infection and Immunity, School of Medicine, Cardiff University and University Hospital of Wales, Cardiff, UK
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Dinkins C, Pilli M, Kehrl JH. Roles of autophagy in HIV infection. Immunol Cell Biol 2014; 93:11-7. [PMID: 25385065 DOI: 10.1038/icb.2014.88] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 08/28/2014] [Accepted: 08/29/2014] [Indexed: 02/07/2023]
Abstract
Autophagy is a major cellular pathway, which at basal levels regulates and maintains the cytoplasmic environment through the capture, isolation and digestion of intracellular materials in a specialized structure called an autophagosome. The unique ability of autophagy to degrade large targets, such as damaged and surplus organelles, intracellular microbes and protein aggregates, has made it a prime focus in inflammation and microbial research. Indeed, autophagy has been shown to be involved in a number of infectious and inflammatory pathologies, by which it may confer protection against intracellular microbes, be targeted by microbes for evasion or be hijacked for microbe biogenesis. In addition, autophagy helps regulate the intracellular and global immune response to both extracellular and intracellular pathogens. Here we review the current literature on the interactions between autophagy and HIV among different immune cells and discuss new research that re-emphasizes the role of inflammation in HIV-mediated CD4(+) T cell death.
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Affiliation(s)
- Christina Dinkins
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Manohar Pilli
- Center for Advanced Sensor Technology, University of Maryland Baltimore County, Baltimore, MD, USA
| | - John H Kehrl
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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