Dissecting How CD4 T Cells Are Lost During HIV Infection
2016; Cell Press; Volume: 19; Issue: 3 Linguagem: Inglês
10.1016/j.chom.2016.02.012
ISSN1934-6069
AutoresGilad Doitsh, Warner C. Greene,
Tópico(s)Inflammasome and immune disorders
ResumoAlthough the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis. Although the replicative life cycle of HIV within CD4 T cells is understood in molecular detail, less is known about how this human retrovirus promotes the loss of CD4 T lymphocytes. It is this cell death process that drives clinical progression to acquired immune deficiency syndrome (AIDS). Recent studies have highlighted how abortive infection of resting and thus nonpermissive CD4 T cells in lymphoid tissues triggers a lethal innate immune response against the incomplete DNA products generated by inefficient viral reverse transcription in these cells. Sensing of these DNA fragments results in pyroptosis, a highly inflammatory form of programmed cell death, that potentially further perpetuates chronic inflammation and immune activation. As discussed here, these studies cast CD4 T cell death during HIV infection in a different light. Further, they identify drug targets that may be exploited to both block CD4 T cell demise and the chronic inflammatory response generated during pyroptosis. During the last three decades, HIV virologists have sought to understand how HIV attacks and destroys its principal cellular target, the CD4 T lymphocyte. It is the death of this subset of lymphocytes that lies at the root of AIDS. Initially, depletion was thought to reflect a viral cytopathic effect occurring in productively infected CD4 T cells (Alimonti et al., 2003Alimonti J.B. Ball T.B. Fowke K.R. Mechanisms of CD4+ T lymphocyte cell death in human immunodeficiency virus infection and AIDS.J. Gen. Virol. 2003; 84: 1649-1661Crossref PubMed Scopus (196) Google Scholar). This notion found support in studies involving immortalized T cell lines or activated cultures of peripheral blood cells. Infection of these cells with laboratory-adapted strains of HIV resulted in productive infection and ultimately apoptotic death of the virus-producing cells. However, the frequency of these activated CD4 T cells appeared too limited to explain the massive loss of CD4 T cells observed in vivo (Jekle et al., 2003Jekle A. Keppler O.T. De Clercq E. Schols D. Weinstein M. Goldsmith M.A. In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells.J. Virol. 2003; 77: 5846-5854Crossref PubMed Scopus (84) Google Scholar, Meyaard et al., 1992Meyaard L. Otto S.A. Jonker R.R. Mijnster M.J. Keet R.P. Miedema F. Programmed death of T cells in HIV-1 infection.Science. 1992; 257: 217-219Crossref PubMed Google Scholar, Muro-Cacho et al., 1995Muro-Cacho C.A. Pantaleo G. Fauci A.S. Analysis of apoptosis in lymph nodes of HIV-infected persons. Intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden.J. Immunol. 1995; 154: 5555-5566PubMed Google Scholar). Other studies suggested that most of the dying cells in lymph nodes of infected patients were bystander CD4 T cells that themselves were not actively infected (Finkel et al., 1995Finkel T.H. Tudor-Williams G. Banda N.K. Cotton M.F. Curiel T. Monks C. Baba T.W. Ruprecht R.M. Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.Nat. Med. 1995; 1: 129-134Crossref PubMed Google Scholar). Various mechanisms have been proposed to contribute to the death of these bystander cells, including the action of host factors (e.g., tumor necrosis factor-α, Fas ligand, and TRAIL [Gandhi et al., 1998Gandhi R.T. Chen B.K. Straus S.E. Dale J.K. Lenardo M.J. Baltimore D. HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism.J. Exp. Med. 1998; 187: 1113-1122Crossref PubMed Scopus (140) Google Scholar, Herbeuval et al., 2005Herbeuval J.P. Grivel J.C. Boasso A. Hardy A.W. Chougnet C. Dolan M.J. Yagita H. Lifson J.D. Shearer G.M. CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis.Blood. 2005; 106: 3524-3531Crossref PubMed Scopus (133) Google Scholar]), and various viral factors (e.g., HIV-1 Tat, Vpr, and Nef) released from infected cells (Schindler et al., 2006Schindler M. Münch J. Kutsch O. Li H. Santiago M.L. Bibollet-Ruche F. Müller-Trutwin M.C. Novembre F.J. Peeters M. Courgnaud V. et al.Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1.Cell. 2006; 125: 1055-1067Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar, Westendorp et al., 1995Westendorp M.O. Frank R. Ochsenbauer C. Stricker K. Dhein J. Walczak H. Debatin K.M. Krammer P.H. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120.Nature. 1995; 375: 497-500Crossref PubMed Google Scholar). For example, the release of exosomes containing the viral accessory protein Nef from HIV-infected cells was shown to cause death of bystander CD4 T cells in vitro (Lenassi et al., 2010Lenassi M. Cagney G. Liao M. Vaupotic T. Bartholomeeusen K. Cheng Y. Krogan N.J. Plemenitas A. Peterlin B.M. HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells.Traffic. 2010; 11: 110-122Crossref PubMed Scopus (147) Google Scholar). Considerable interest has also focused on the role of gp120 Env protein in bystander killing, suggesting death signals involve gp120 binding to its chemokine receptor or occur through subsequent gp41-mediated fusion events (Perfettini et al., 2005Perfettini J.L. Castedo M. Roumier T. Andreau K. Nardacci R. Piacentini M. Kroemer G. Mechanisms of apoptosis induction by the HIV-1 envelope.Cell Death Differ. 2005; 12: 916-923Crossref PubMed Scopus (96) Google Scholar). It should be noted that not all CD4-expressing cells are rapidly depleted by HIV. For example, monocyte-derived macrophages do not die quickly; instead they produce virus over a period of weeks (Cassol et al., 2006Cassol E. Alfano M. Biswas P. Poli G. Monocyte-derived macrophages and myeloid cell lines as targets of HIV-1 replication and persistence.J. Leukoc. Biol. 2006; 80: 1018-1030Crossref PubMed Scopus (72) Google Scholar). Infected microglia appear to survive for months if not years (Jones and Power, 2006Jones G. Power C. Regulation of neural cell survival by HIV-1 infection.Neurobiol. Dis. 2006; 21: 1-17Crossref PubMed Scopus (66) Google Scholar). These findings suggest that viral infection and replication are not inherently linked with cell death. Indeed, it is well known that many retroviruses infect cells without killing their hosts (Swanstrom and Coffin, 2012Swanstrom R. Coffin J. HIV-1 pathogenesis: the virus.Cold Spring Harb. Perspect. Med. 2012; 2: a007443Crossref Scopus (18) Google Scholar). Unlike non-enveloped viruses that usually exit infected cells by inducing their lysis, enveloped viruses leave their cellular hosts by budding keeping the plasma membrane intact. Therefore, other features of HIV and its interaction with the host must be responsible for the massive CD4 T cell loss in AIDS. In contrast to the productive infection and direct killing observed with activated blood CD4 T cells and CD4 T cell lines, studies of HIV infection employing primary lymphoid tissue highlighted a key role of death occurring within the bystander cell population (Finkel et al., 1995Finkel T.H. Tudor-Williams G. Banda N.K. Cotton M.F. Curiel T. Monks C. Baba T.W. Ruprecht R.M. Kupfer A. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes.Nat. Med. 1995; 1: 129-134Crossref PubMed Google Scholar, Jekle et al., 2003Jekle A. Keppler O.T. De Clercq E. Schols D. Weinstein M. Goldsmith M.A. In vivo evolution of human immunodeficiency virus type 1 toward increased pathogenicity through CXCR4-mediated killing of uninfected CD4 T cells.J. Virol. 2003; 77: 5846-5854Crossref PubMed Scopus (84) Google Scholar, Rosok et al., 1997Rosok B. Brinchmann J.E. Voltersvik P. Olofsson J. Bostad L. Asjö B. Correlates of latent and productive HIV type-1 infection in tonsillar CD4(+) T cells.Proc. Natl. Acad. Sci. USA. 1997; 94: 9332-9336Crossref PubMed Scopus (21) Google Scholar). We have explored HIV-associated CD4 T cell death using an ex vivo human lymphoid aggregate culture (HLAC) system formed with fresh human tonsil or spleen tissues (Glushakova et al., 1995Glushakova S. Baibakov B. Margolis L.B. Zimmerberg J. Infection of human tonsil histocultures: a model for HIV pathogenesis.Nat. Med. 1995; 1: 1320-1322Crossref PubMed Google Scholar). This system recapitulates many of the conditions encountered by HIV in vivo and, thus, offers a biologically relevant approach for modeling the molecular and cellular events that occur during HIV infection in vivo. Importantly, HLACs can be infected with a low number of viral particles in the absence of artificial mitogens or cytokine activation, allowing analysis of CD4 T cell death in a natural and preserved lymphoid environment. Infection of HLACs with HIV-1 resulted in the near complete depletion of CD4 T cell population without changes in the CD8 T cell and B cells compartments. However, only approximately 5% of these CD4 T cells became productively infected with the virus. Conversely, 95% of the dying CD4 T cells were resting, nonpermissive CD4 T cells. A key question was how HIV promotes the death of these common bystander cells. To better understand how these bystander cells were dying, antiviral drugs affecting distinct sequential events in the retroviral life cycle were employed. Early experiments revealed that bystander CD4 T cell death is prevented by entry inhibitors (for example, AMD3100 that blocks the engagement of gp120 with CXCR4) and fusion inhibitors (for example, T20 that blocks six-helix bundle formation by gp41, a prerequisite for virion fusion and core insertion). Conversely, cell death was not effectively prevented by a number of nucleoside reverse transcriptase inhibitors (NRTIs) including AZT. These key findings raised the possibility that CD4 T cell death associated with HIV-1 involves a non-productive form of infection of the resting CD4 T cells (Swiggard et al., 2004Swiggard W.J. O’Doherty U. McGain D. Jeyakumar D. Malim M.H. Long HIV type 1 reverse transcripts can accumulate stably within resting CD4+ T cells while short ones are degraded.AIDS Res. Hum. Retroviruses. 2004; 20: 285-295Crossref PubMed Scopus (40) Google Scholar, Zack et al., 1990Zack J.A. Arrigo S.J. Weitsman S.R. Go A.S. Haislip A. Chen I.S. HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure.Cell. 1990; 61: 213-222Abstract Full Text PDF PubMed Scopus (1034) Google Scholar, Zhou et al., 2005Zhou Y. Zhang H. Siliciano J.D. Siliciano R.F. Kinetics of human immunodeficiency virus type 1 decay following entry into resting CD4+ T cells.J. Virol. 2005; 79: 2199-2210Crossref PubMed Scopus (124) Google Scholar). Subsequent studies focused on events that occur after HIV-1 entry. Specifically, our laboratory examined whether blocking early DNA synthesis with non-nucleoside reverse transcriptase inhibitors (NNRTIs) produced the same negative effect as AZT. Strikingly, the NNRTIs efavirenz and nevirapine blocked CD4 T cell death in HIV-infected HLACs as efficiently as entry or fusion inhibitors, suggesting that a certain degree of DNA chain elongation during reverse transcription is required to elicit the cell-death response (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Using independent in vitro assays, viral ssDNA and dsDNA oligonucleotides exceeding 500 bases in length were shown to be sufficient to induce this cell death response. These findings revealing a “death window” associated with the chain elongation phase of reverse transcription suggested a different mechanism of bystander cell death than previously described. Rather than being driven by membrane signaling events through CD4 or chemokine co-receptors, or involving the elaboration of cytotoxic viral proteins or host factors, the cell death observed in these HLACs involved abortive viral infection of the resting CD4 T cells (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). Specifically, HIV binds and effectively fuses to these bystander CD4 T cells; however, because of their resting state, the viral life cycle attenuates during the chain elongation phase of reverse transcription, giving rise to incomplete cytosolic viral DNA transcripts. The accumulation of incomplete reverse transcripts within the abortively infected cells raised the possibility that their death involved innate sensing of these DNAs. Accordingly, affinity chromatography and mass spectroscopy studies were used to identify this cellular sensor. These studies revealed that sensing of the viral DNA fragments was mediated through interferon-gamma-inducible protein 16 (IFI16) (Monroe et al., 2014Monroe K.M. Yang Z. Johnson J.R. Geng X. Doitsh G. Krogan N.J. Greene W.C. IFI16 DNA sensor is required for death of lymphoid CD4 T cells abortively infected with HIV.Science. 2014; 343: 428-432Crossref PubMed Scopus (116) Google Scholar). shRNA-mediated knockdown of IFI16 rescued bystander CD4 T cells from death in HIV-infected HLACs. As discussed below, at present, IFI16 is the only mammalian DNA sensor identified that recognizes both single- and double-stranded (ds) DNA. By examining how these CD4 T cells were dying, our laboratory found that CD4 T cell depletion was blocked in the presence of caspase-1 inhibitors. Similarly, shRNA-mediated knockdown of caspase-1, but not caspase-3, blocked CD4 T cell death in HIV-infected HLAC cultures. These findings indicated that death of abortively infected CD4 T cells in HLACs is elicited by caspase-1-mediated pyroptosis, a highly inflammatory form of programmed cell death (Doitsh et al., 2014Doitsh G. Galloway N.L. Geng X. Yang Z. Monroe K.M. Zepeda O. Hunt P.W. Hatano H. Sowinski S. Muñoz-Arias I. Greene W.C. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.Nature. 2014; 505: 509-514Crossref PubMed Scopus (195) Google Scholar). Consistent with this notion, shRNA knockdown of the inflammasome adaptor protein, ASC (apoptosis-associated speck-like protein containing a CARD) effectively blocked CD4 T cell death. Interestingly, shRNA-mediated knockdown of NLRP3 did not alter cell death, suggesting that cell death is mediated through caspase-1-dependent pyroptosis involving an inflammasome that contains ASC but lacks NLRP3. This finding was consistent with the fact that IFI16 can form its own ASC-containing inflammasome where caspase-1 is activated. Together, these findings revealed a fundamentally different mechanism of CD4 T cell death by HIV, emphasizing that most cells are not dying because of a toxic action of products encoded by HIV. Rather, death occurs as a consequence of a powerful defensive innate immune response launched by the host against the virus leading to a “cellular form of suicide” rather than “virological murder” (Figure 1). This paradox—that pathogenesis is not produced when HIV successfully replicates but instead when it encounters resistance by the host and fails to replicate—raises new questions. What immune cells and tissues are involved in HIV pathogenesis? Why are some lentiviral infections pathogenic and others nonpathogenic? What role does pyroptosis play in the chronic inflammation observed during HIV infection? Does pyroptosis play any role in the residual inflammation observed in HIV patients treated with antiretroviral therapy (ART)? Because the pyroptotic death pathway was readily detected in HLAC formed with human tonsil or spleen, subsequent studies investigated whether resting CD4 T cells circulating in the blood are similarly sensitive to pyroptosis in the presence of HIV. Remarkably, although quiescent lymphoid and blood CD4 T cells supported HIV entry and fusion with equivalent efficiency (Cavrois et al., 2011Cavrois M. Neidleman J. Galloway N. Derdeyn C.A. Hunter E. Greene W.C. Measuring HIV fusion mediated by envelopes from primary viral isolates.Methods. 2011; 53: 34-38Crossref PubMed Scopus (4) Google Scholar), blood cells were highly resistant to the pyroptotic death pathway (Muñoz-Arias et al., 2015Muñoz-Arias I. Doitsh G. Yang Z. Sowinski S. Ruelas D. Greene W.C. Blood-Derived CD4 T Cells Naturally Resist Pyroptosis during Abortive HIV-1 Infection.Cell Host Microbe. 2015; 18: 463-470Abstract Full Text Full Text PDF PubMed Google Scholar). At least in part, this difference reflects their deeper state of cellular rest. This deeper resting state is associated with the formation of fewer incomplete reverse transcripts following abortive infection and lower expression of innate immune sensors, specifically IFI16 (Figure 2A) (Muñoz-Arias et al., 2015Muñoz-Arias I. Doitsh G. Yang Z. Sowinski S. Ruelas D. Greene W.C. Blood-Derived CD4 T Cells Naturally Resist Pyroptosis during Abortive HIV-1 Infection.Cell Host Microbe. 2015; 18: 463-470Abstract Full Text Full Text PDF PubMed Google Scholar). Pyroptosis involves multiple events and an array of endogenous DNA sensors and innate immune mediators, such as ASC, NLRP3, and cytoplasmic pro-IL-1β, that are constitutively expressed in lymphoid tissue CD4 T cells (Doitsh et al., 2014Doitsh G. Galloway N.L. Geng X. Yang Z. Monroe K.M. Zepeda O. Hunt P.W. Hatano H. Sowinski S. Muñoz-Arias I. Greene W.C. Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection.Nature. 2014; 505: 509-514Crossref PubMed Scopus (195) Google Scholar). Resting blood-derived CD4 T cells lack the expression of these key components, likely further contributing to their resistance for pyroptosis. Interestingly, when these blood cells are activated, higher levels of IFI16 are detected, reverse transcription improves, yet the cells still display resistance to pyroptosis, arguing for yet additional blocks. The pyroptotic response is not the only arm of IFI16 signaling that is defective. Within these activated blood CD4 T cells, IFI16 effectively recruits STING and TBK1 following sensing of DNA. However, this response does not lead to the expression of IFNβ- and IFN-stimulated genes (Berg et al., 2014Berg R.K. Rahbek S.H. Kofod-Olsen E. Holm C.K. Melchjorsen J. Jensen D.G. Hansen A.L. Jørgensen L.B. Ostergaard L. Tolstrup M. et al.T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication.PLoS ONE. 2014; 9: e84513Crossref PubMed Scopus (10) Google Scholar). Thus, IFI16 may be involved in a yet higher level of regulation in CD4 T cells. Such regulation may allow IFI16-mediated function in select tissue compartments but not in others, perhaps serving to prevent inappropriate cell-autonomous responses. These findings highlight a striking difference in the biology of resting CD4 T cells residing in lymphoid tissue versus blood. Finally, the primary experimental use of mitogen-activated blood CD4 T cells for the study of HIV pathogenesis may have inadvertently created observational bias favoring the direct killing model, in which activated CD4 T cells are productively infected with HIV-1 and die via caspase-3-mediated apoptosis (Cooper et al., 2013Cooper A. García M. Petrovas C. Yamamoto T. Koup R.A. Nabel G.J. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration.Nature. 2013; 498: 376-379Crossref PubMed Scopus (75) Google Scholar, Gandhi et al., 1998Gandhi R.T. Chen B.K. Straus S.E. Dale J.K. Lenardo M.J. Baltimore D. HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism.J. Exp. Med. 1998; 187: 1113-1122Crossref PubMed Scopus (140) Google Scholar, Laurent-Crawford et al., 1991Laurent-Crawford A.G. Krust B. Muller S. Rivière Y. Rey-Cuillé M.A. Béchet J.M. Montagnier L. Hovanessian A.G. 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While in the lymph nodes, CD4 T cells are in intimate contact with other cells and exposed to various cytokines. One consequence of this interaction is that a small subpopulation of these cells achieves a sufficient state of cellular activation to support productive HIV infection (Kreisberg et al., 2006Kreisberg J.F. Yonemoto W. Greene W.C. Endogenous factors enhance HIV infection of tissue naive CD4 T cells by stimulating high molecular mass APOBEC3G complex formation.J. Exp. Med. 2006; 203: 865-870Crossref PubMed Scopus (87) Google Scholar). In contrast, CD4 T cells in the blood are not exposed to these cytokines, and most of these cells remain in a deep resting state that is unable to support productive HIV infection (Gao et al., 1993Gao W.Y. Cara A. Gallo R.C. Lori F. Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication.Proc. Natl. Acad. Sci. USA. 1993; 90: 8925-8928Crossref PubMed Scopus (0) Google Scholar). Innate immune mediators and the microenvironment within lymphoid tissues are evidently crucial in the massive bystander killing of CD4 T cells that occurs during HIV infection (Figure 2B). Remarkably, when cocultured with either CD4 or CD8 T cells or B cells from lymphoid tissues, normally resistant peripheral blood CD4 T cells readily died from caspase-1-induced pyroptosis (Figure 2C). Currently, the nature of sensitization is poorly defined. These effects are quickly lost when the cocultures are disassembled, which resembles CD4 T cells trafficking in and out of lymphoid tissues where they rapidly gain and lose sensitivity to pyroptosis (Muñoz-Arias et al., 2015Muñoz-Arias I. Doitsh G. Yang Z. Sowinski S. Ruelas D. Greene W.C. Blood-Derived CD4 T Cells Naturally Resist Pyroptosis during Abortive HIV-1 Infection.Cell Host Microbe. 2015; 18: 463-470Abstract Full Text Full Text PDF PubMed Google Scholar). Conditioned medium from lymphoid tissues fails to consistently render peripheral blood cells sensitive to cell death by pyroptosis, suggesting that key signals are generated through cell-to-cell interactions. It is still unclear whether one or multiple signals are required. By understanding the nature of the signaling between lymphoid tissue and blood cells, it might be possible to use antibodies or small molecules to block sensitization in lymphoid tissues, thereby rendering all CD4 T cells resistant to pyroptosis, like blood CD4 T cells. However, it would be key to assess the effects of such an intervention on the normal human immune response to ensure that one form of immunodeficiency is not replaced by another. Retroviruses fuse and enter their target cells either as cell-free virions or through cell-to-cell spread (Sattentau, 2010Sattentau Q.J. Cell-to-Cell Spread of Retroviruses.Viruses. 2010; 2: 1306-1321Crossref PubMed Scopus (46) Google Scholar). The pathway utilized greatly affects the infectivity yield. Cell-to-cell spread is 102 to 103 times more efficient than cell-free particles emanating from the same cells (Jolly, 2011Jolly C. Cell-to-cell transmission of retroviruses: Innate immunity and interferon-induced restriction factors.Virology. 2011; 411: 251-259Crossref PubMed Scopus (10) Google Scholar). Although the increased effectiveness of cell-to-cell spread has been known for 20 years (Dimitrov et al., 1993Dimitrov D.S. Willey R.L. Sato H. Chang L.J. Blumenthal R. Martin M.A. Quantitation of human immunodeficiency virus type 1 infection kinetics.J. Virol. 1993; 67: 2182-2190Crossref PubMed Google Scholar), its contribution to HIV pathogenesis—and particularly to abortive infection, innate immune detection, and pyroptosis—had not been directly explored. Remarkably, our studies in HLACs show that the mode of viral spread sharply affects the outcome of HIV infection. Infection with free HIV-1 particles, even at high quantities, is unable to trigger innate immune recognition and pyroptotic cell death. However, these free virions are able to establish productive infection in a small subset of activated CD4 T cells that die via caspase-3-dependent apoptosis after producing new virions. Conversely, cell-to-cell spread of HIV-1 across virological synapse leads to massive abortive infection of the far more prevalent resting non-permissive CD4 T cells. These cells ultimately die as a consequence of caspase-1-dependent pyroptosis (Galloway et al., 2015Galloway N.L. Doitsh G. Monroe K.M. Yang Z. Muñoz-Arias I. Levy D.N. Greene W.C. Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells.Cell Rep. 2015; 12: 1555-1563Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). These findings differ from the prevailing view of HIV pathogenesis—where most of the pathogenic effects of HIV arise from the killing of CD4 T cells by circulating free virions. Instead, we propose that the fundamental “killing units” that lead to CD4 T cell depletion and progression
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