HIV integrase and the swan song of the CD4 T cells?

Retrovirology

Mireille Laforge¹  John Zaunders²  Jérôme Estaquier³ 

[1] CNRS FRE 3235, Université Paris Descartes, Paris, France;St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Darlinghurst, NSW, Australia;Université Laval, Centre de Recherche en Infectiologie, Québec, Canada

关键词: DNA-PK;    p53;    DNA;    Apoptosis;    HIV;   

Others  :  805934
DOI  :  10.1186/1742-4690-10-149

 received in 2013-08-12, accepted in 2013-11-06,  发布年份 2013

【 摘 要 】

T cell apoptosis represents one pathophysiological mechanism associated with AIDS. Herein, we discuss the recent report published by A. Cooper et al. in Nature (June 2013) regarding HIV viral DNA integration-mediated apoptosis.

【 授权许可】

   
2013 Estaquier et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Ameisen JC, Estaquier J, Idziorek T: From AIDS to parasite infection: pathogen-mediated subversion of programmed cell death as a mechanism for immune dysregulation. Immunol Rev 1994, 142:9-51.
• [2]Ameisen JC, Capron A: Cell dysfunction and depletion in AIDS: the programmed cell death hypothesis. Immunol Today 1991, 12:102-105.
• [3]Terai C, Kornbluth RS, Pauza CD, Richman DD, Carson DA: Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1. J Clin Invest 1991, 87:1710-1715.
• [4]Laurent-Crawford AG, Krust B, Muller S, Riviere Y, Rey-Cuille MA, Bechet JM, Montagnier L, Hovanessian AG: The cytopathic effect of HIV is associated with apoptosis. Virology 1991, 185:829-839.
• [5]Gandhi RT, Chen BK, Straus SE, Dale JK, Lenardo MJ, Baltimore D: HIV-1 directly kills CD4+ T cells by a Fas-independent mechanism. J Exp Med 1998, 187:1113-1122.
• [6]Petit F, Arnoult D, Lelievre JD, Moutouh-de Parseval L, Hance AJ, Schneider P, Corbeil J, Ameisen JC, Estaquier J: Productive HIV-1 infection of primary CD4+ T cells induces mitochondrial membrane permeabilization leading to a caspase-independent cell death. J Biol Chem 2002, 277:1477-1487.
• [7]Lenardo MJ, Angleman SB, Bounkeua V, Dimas J, Duvall MG, Graubard MB, Hornung F, Selkirk MC, Speirs CK, Trageser C, Orenstein JO, Bolton DL: Cytopathic killing of peripheral blood CD4(+) T lymphocytes by human immunodeficiency virus type 1 appears necrotic rather than apoptotic and does not require env. J Virol 2002, 76:5082-5093.
• [8]Moutouh L, Estaquier J, Richman DD, Corbeil J: Molecular and cellular analysis of human immunodeficiency virus-induced apoptosis in lymphoblastoid T-cell-line-expressing wild-type and mutated CD4 receptors. J Virol 1998, 72:8061-8072.
• [9]Lelievre JD, Petit F, Perrin L, Mammano F, Arnoult D, Ameisen JC, Corbeil J, Gervaix A, Estaquier J: The density of coreceptors at the surface of CD4+ T cells contributes to the extent of human immunodeficiency virus type 1 viral replication-mediated T cell death. AIDS Res Hum Retroviruses 2004, 20:1230-1243.
• [10]Laforge M, Petit F, Estaquier J, Senik A: Commitment to apoptosis in CD4(+) T lymphocytes productively infected with human immunodeficiency virus type 1 is initiated by lysosomal membrane permeabilization, itself induced by the isolated expression of the viral protein Nef. J Virol 2007, 81:11426-11440.
• [11]Thornberry NA, Lazebnik Y: Caspases: enemies within. Science 1998, 281:1312-1316.
• [12]Cooper A, Garcia M, Petrovas C, Yamamoto T, Koup RA, Nabel GJ: HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature 2013, 498:376-379.
• [13]Li L, Olvera JM, Yoder KE, Mitchell RS, Butler SL, Lieber M, Martin SL, Bushman FD: Role of the non-homologous DNA end joining pathway in the early steps of retroviral infection. Embo J 2001, 20:3272-3281.
• [14]Doitsh G, Cavrois M, Lassen KG, Zepeda O, Yang Z, Santiago ML, Hebbeler AM, Greene WC: Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue. Cell 2010, 143:789-801.
• [15]Grivel JC, Margolis LB: CCR5- and CXCR4-tropic HIV-1 are equally cytopathic for their T-cell targets in human lymphoid tissue. Nat Med 1999, 5:344-346.
• [16]Petit F, Corbeil J, Lelievre JD, Moutouh-de Parseval L, Pinon G, Green DR, Ameisen JC, Estaquier J: Role of CD95-activated caspase-1 processing of IL-1beta in TCR-mediated proliferation of HIV-infected CD4(+) T cells. Eur J Immunol 2001, 31:3513-3524.
• [17]Daniel R, Katz RA, Skalka AM: A role for DNA-PK in retroviral DNA integration. Science 1999, 284:644-647.
• [18]Ariumi Y, Turelli P, Masutani M, Trono D: DNA damage sensors ATM, ATR, DNA-PKcs, and PARP-1 are dispensable for human immunodeficiency virus type 1 integration. J Virol 2005, 79:2973-2978.
• [19]Baekelandt V, Claeys A, Cherepanov P, De Clercq E, De Strooper B, Nuttin B, Debyser Z: DNA-Dependent protein kinase is not required for efficient lentivirus integration. J Virol 2000, 74:11278-11285.
• [20]Lau A, Swinbank KM, Ahmed PS, Taylor DL, Jackson SP, Smith GC, O'Connor MJ: Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase. Nat Cell Biol 2005, 7:493-500.
• [21]Genini D, Sheeter D, Rought S, Zaunders JJ, Susin SA, Kroemer G, Richman DD, Carson DA, Corbeil J, Leoni LM: HIV induces lymphocyte apoptosis by a p53-initiated, mitochondrial- mediated mechanism. Faseb J 2001, 15:5-6.
• [22]Imbeault M, Giguere K, Ouellet M, Tremblay MJ: Exon level transcriptomic profiling of HIV-1-infected CD4(+) T cells reveals virus-induced genes and host environment favorable for viral replication. PLoS Pathog 2010, 8:e1002861.
• [23]Laforge M, Limou S, Harper F, Casartelli N, Rodrigues V, Silvestre R, Haloui H, Zagury JF, Senik A, Estaquier J: DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV. PLoS Pathog 2013, 9:e1003328.
• [24]Haase AT: Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol 1999, 17:625-656.
• [25]Koelsch KK, Liu L, Haubrich R, May S, Havlir D, Gunthard HF, Ignacio CC, Campos-Soto P, Little SJ, Shafer R, Robbins GK, D'Aquila RT, Kawano Y, Young K, Dao P, Spina CA, Richman DD, Wong JK: Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis 2008, 197:411-419.
• [26]Siliciano JD, Kajdas J, Finzi D, Quinn TC, Chadwick K, Margolick JB, Kovacs C, Gange SJ, Siliciano RF: Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med 2003, 9:727-728.
• [27]Hurtrel B, Petit F, Arnoult D, Muller-Trutwin M, Silvestri G, Estaquier J: Apoptosis in SIV infection. Cell Death Differ 2005, 12(Suppl 1):979-990.
• [28]Estaquier J, Idziorek T, de Bels F, Barre-Sinoussi F, Hurtrel B, Aubertin AM, Venet A, Mehtali M, Muchmore E, Michel P, et al.: Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc Natl Acad Sci USA 1994, 91:9431-9435.
• [29]Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, McClure HM, Staprans SI, Feinberg MB: Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 2003, 18:441-452.
• [30]Gougeon ML, Lecoeur H, Boudet F, Ledru E, Marzabal S, Boullier S, Roue R, Nagata S, Heeney J: Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype. J Immunol 1997, 158:2964-2976.
• [31]Monceaux V, Estaquier J, Fevrier M, Cumont MC, Riviere Y, Aubertin AM, Ameisen JC, Hurtrel B: Extensive apoptosis in lymphoid organs during primary SIV infection predicts rapid progression towards AIDS. Aids 2003, 17:1585-1596.
• [32]Viollet L, Monceaux V, Petit F, Ho Tsong Fang R, Cumont MC, Hurtrel B, Estaquier J: Death of CD4+ T cells from lymph nodes during primary SIVmac251 infection predicts the rate of AIDS progression. J Immunol 2006, 177:6685-6694.
• [33]Cumont MC, Diop O, Vaslin B, Elbim C, Viollet L, Monceaux V, Lay S, Silvestri G, Le Grand R, Muller-Trutwin M, Hurtrel B, Estaquier J: Early divergence in lymphoid tissue apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates. J Virol 2008, 82:1175-1184.
• [34]Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A: Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes [see comments]. Nat Med 1995, 1:129-134.
• [35]Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT: Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 2005, 434:1148-1152.
• [36]Campillo-Gimenez L, Laforge M, Fay M, Brussel A, Cumont MC, Monceaux V, Diop O, Levy Y, Hurtrel B, Zaunders J, Corbeil J, Elbim C, Estaquier J: Nonpathogenesis of simian immunodeficiency virus infection is associated with reduced inflammation and recruitment of plasmacytoid dendritic cells to lymph nodes, not to lack of an interferon type I response, during the acute phase. J Virol 2010, 84:1838-1846.
• [37]Campillo-Gimenez L, Cumont MC, Fay M, Kared H, Monceaux V, Diop O, Muller-Trutwin M, Hurtrel B, Levy Y, Zaunders J, Dy M, Leite-de-Moraes MC, Elbim C, Estaquier J: AIDS progression is associated with the emergence of IL-17-producing cells early after simian immunodeficiency virus infection. J Immunol 2010, 184:984-992.
• [38]Benveniste O, Flahault A, Rollot F, Elbim C, Estaquier J, Pedron B, Duval X, Dereuddre-Bosquet N, Clayette P, Sterkers G, Simon A, Ameisen JC, Leport C: Mechanisms involved in the low-level regeneration of CD4+ cells in HIV-1-infected patients receiving highly active antiretroviral therapy who have prolonged undetectable plasma viral loads. J Infect Dis 2005, 191:1670-1679.
• [39]Villinger F, Folks TM, Lauro S, Powell JD, Sundstrom JB, Mayne A, Ansari AA: Immunological and virological studies of natural SIV infection of disease-resistant nonhuman primates. Immunol Lett 1996, 51:59-68.
• [40]Chakrabarti LA, Luckay A, Marx PA: A divergent simian immunodeficiency virus from sooty mangabey with an atypical Tat-TAR structure. AIDS Res Hum Retroviruses 2001, 17:1155-1165.
• [41]Paiardini M, Cervasi B, Reyes-Aviles E, Micci L, Ortiz AM, Chahroudi A, Vinton C, Gordon SN, Bosinger SE, Francella N, Hallberg PL, Cramer E, Schlub T, Chan ML, Riddick NE, Collman RG, Apetrei C, Pandrea I, Else J, Munch J, Kirchhoff F, Davenport MP, Brenchley JM, Silvestri G: Low levels of SIV infection in sooty mangabey central memory CD(4)(+) T cells are associated with limited CCR5 expression. Nat Med 2011, 17:830-836.
• [42]Katsikis PD, Wunderlich ES, Smith CA, Herzenberg LA: Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 1995, 181:2029-2036.
• [43]Estaquier J, Idziorek T, Zou W, Emilie D, Farber CM, Bourez JM, Ameisen JC: T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)- mediated apoptosis of CD4+ T cells from human immunodeficiency virus- infected persons. J Exp Med 1995, 182:1759-1767.
• [44]Estaquier J, Tanaka M, Suda T, Nagata S, Golstein P, Ameisen JC: Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists. Blood 1996, 87:4959-4966.
• [45]Baumler CB, Bohler T, Herr I, Benner A, Krammer PH, Debatin KM: Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children. Blood 1996, 88:1741-1746.
• [46]Arnoult D, Petit F, Lelievie JD, Lecossier D, Hance A, Monceaux V, Ho Tsong Fang R, Huntrel B, Ameisen JC, Estaquier J: Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression. Cell Death Differ 2003, 10:1240-1252.
• [47]Badley AD, Dockrell DH, Algeciras A, Ziesmer S, Landay A, Lederman MM, Connick E, Kessler H, Kuritzkes D, Lynch DH, Roche P, Yagita H, Paya CV: In vivo analysis of Fas/FasL interactions in HIV-infected patients. J Clin Invest 1998, 102:79-87.
• [48]Algeciras A, Dockrell DH, Lynch DH, Paya CV: CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor- mediated apoptosis. J Exp Med 1998, 187:711-720.
• [49]Laforge M, Campillo-Gimenez L, Monceaux V, Cumont MC, Hurtrel B, Corbeil J, Zaunders J, Elbim C, Estaquier J: HIV/SIV infection primes monocytes and dendritic cells for apoptosis. PLoS Pathog 2011, 7:e1002087.
• [50]Herbeuval JP, Boasso A, Grivel JC, Hardy AW, Anderson SA, Dolan MJ, Chougnet C, Lifson JD, Shearer GM: TNF-related apoptosis-inducing ligand (TRAIL) in HIV-1-infected patients and its in vitro production by antigen-presenting cells. Blood 2005, 105:2458-2464.
• [51]Lecossier D, Bouchonnet F, Schneider P, Clavel F, Hance AJ: Discordant increases in CD4+ T cells in human immunodeficiency virus- infected patients experiencing virologic treatment failure: role of changes in thymic output and T cell death. J Infect Dis 2001, 183:1009-1016.
• [52]Chehimi J, Papasavvas E, Tomescu C, Gekonge B, Abdulhaqq S, Raymond A, Hancock A, Vinekar K, Carty C, Reynolds G, Pistilli M, Mounzer K, Kostman J, Montaner LJ: Inability of plasmacytoid dendritic cells to directly lyse HIV-infected autologous CD4+ T cells despite induction of tumor necrosis factor-related apoptosis-inducing ligand. J Virol 2010, 84:2762-2773.
• [53]Weant AE, Michalek RD, Khan IU, Holbrook BC, Willingham MC, Grayson JM: Apoptosis regulators Bim and Fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 2008, 28:218-230.
• [54]Hutcheson J, Scatizzi JC, Siddiqui AM, Haines GK 3rd, Wu T, Li QZ, Davis LS, Mohan C, Perlman H: Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 2008, 28:206-217.
• [55]Hughes PD, Belz GT, Fortner KA, Budd RC, Strasser A, Bouillet P: Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 2008, 28:197-205.
• [56]van Grevenynghe J, Procopio FA, He Z, Chomont N, Riou C, Zhang Y, Gimmig S, Boucher G, Wilkinson P, Shi Y, Yassine-Diab B, Said EA, Trautmann L, El Far M, Balderas RS, Boulassel MR, Routy JP, Haddad EK, Sekaly RP: Transcription factor FOXO3a controls the persistence of memory CD4(+) T cells during HIV infection. Nat Med 2008, 14:266-274.
• [57]Markowitz M, Vaida F, Hare CB, Boden D, Mohri H, Hecht FM, Kalayjian RC, Conrad A, Mildvan D, Aberg J, Hogan C, Kilby JM, Balfour HH Jr, Schafer K, Richman D, Little S: The virologic and immunologic effects of cyclosporine as an adjunct to antiretroviral therapy in patients treated during acute and early HIV-1 infection. J Infect Dis 2010, 201:1298-1302.
• [58]Ameisen JC, Estaquier J, Idziorek T, De Bels F: The relevance of apoptosis to AIDS pathogenesis. Trends Cell Biol 1995, 5:27-32.
• [59]Clerici M, Sarin A, Coffman RL, Wynn TA, Blatt SP, Hendrix CW, Wolf SF, Shearer GM, Henkart PA: Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis. Proc Natl Acad Sci USA 1994, 91:11811-11815.
• [60]Cumont MC, Monceaux V, Viollet L, Lay S, Parker R, Hurtrel B, Estaquier J: TGF-beta in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus. Cell Death Differ 2007, 14:1747-1758.
• [61]Chehimi J, Marshall JD, Salvucci O, Frank I, Chehimi S, Kawecki S, Bacheller D, Rifat S, Chouaib S: IL-15 enhances immune functions during HIV infection. J Immunol 1997, 158:5978-5987.
• [62]Mueller YM, Makar V, Bojczuk PM, Witek J, Katsikis PD: IL-15 enhances the function and inhibits CD95/Fas-induced apoptosis of human CD4+ and CD8+ effector-memory T cells. Int Immunol 2003, 15:49-58.
• [63]Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, Darbyshire J, Emery S, Fox L, Gordin F, Lane HC, Lundgren JD, Mitsuyasu R, Neaton JD, Phillips A, Routy JP, Tambussi G, Wentworth D: Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009, 361:1548-1559.
• [64]Garibal J, Laforge M, Silvestre R, Mouhamad S, Campillo-Gimenez L, Levy Y, Estaquier J: IL-2 immunotherapy in chronically SIV-infected Rhesus macaques. Virol J 2012, 9:220. BioMed Central Full Text
• [65]Zaunders JJ, Moutouh-de Parseval L, Kitada S, Reed JC, Rought S, Genini D, Leoni L, Kelleher A, Cooper DA, Smith DE, Grey P, Estaquier J, Little S, Richman DD, Corbeil J: Polyclonal proliferation and apoptosis of CCR5+ T lymphocytes during primary human immunodeficiency virus type 1 infection: regulation by interleukin (IL)-2, IL-15, and Bcl-2. J Infect Dis 2003, 187:1735-1747.
• [66]Verhoeyen E, Dardalhon V, Ducrey-Rundquist O, Trono D, Taylor N, Cosset FL: IL-7 surface-engineered lentiviral vectors promote survival and efficient gene transfer in resting primary T lymphocytes. Blood 2003, 101:2167-2174.
• [67]Scripture-Adams DD, Brooks DG, Korin YD, Zack JA: Interleukin-7 induces expression of latent human immunodeficiency virus type 1 with minimal effects on T-cell phenotype. J Virol 2002, 76:13077-13082.
• [68]Vassena L, Proschan M, Fauci AS, Lusso P: Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+ and CD8+ T cells from HIV-1-infected individuals. Proc Natl Acad Sci USA 2007, 104:2355-2360.
• [69]Brieu N, Portales P, Carles MJ, Corbeau P: Interleukin-7 induces HIV type 1 R5-to-X4 switch. Blood 2011, 117:2073-2074.
• [70]Lelievre JD, Petit F, Arnoult D, Ameisen JC, Estaquier J: Interleukin 7 increases human immunodeficiency virus type 1 LAI-mediated Fas-induced T-cell death. J Virol 2005, 79:3195-3199.
• [71]Nunnari G, Xu Y, Acheampong EA, Fang J, Daniel R, Zhang C, Zhang H, Mukhtar M, Pomerantz RJ: Exogenous IL-7 induces Fas-mediated human neuronal apoptosis: potential effects during human immunodeficiency virus type 1 infection. J Neurovirol 2005, 11:319-328.
• [72]Fluur C, De Milito A, Fry TJ, Vivar N, Eidsmo L, Atlas A, Federici C, Matarrese P, Logozzi M, Rajnavolgyi E, Mackall CL, Fais S, Chiodi F, Rethi B: Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol 2007, 178:5340-5350.
• [73]Banda NK, Bernier J, Kurahara DK, Kurrle R, Haigwood N, Sekaly RP, Finkel TH: Crosslinking CD4 by human immunodeficiency virus gp120 primes T cells for activation-induced apoptosis. J Exp Med 1992, 176:1099-1106.
• [74]Oyaizu N, McCloskey TW, Coronesi M, Chirmule N, Kalyanaraman VS, Pahwa S: Accelerated apoptosis in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus type-1 infected patients and in CD4 cross-linked PBMCs from normal individuals. Blood 1993, 82:3392-3400.
• [75]Oyaizu N, McCloskey TW, Than S, Hu R, Kalyanaraman VS, Pahwa S: Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. Blood 1994, 84:2622-2631.
• [76]Kameoka M, Kimura T, Zheng YH, Suzuki S, Fujinaga K, Luftig RB, Ikuta K: Protease-defective, gp120-containing human immunodeficiency virus type 1 particles induce apoptosis more efficiently than does wild-type virus or recombinant gp120 protein in healthy donor-derived peripheral blood T cells. J Clin Microbiol 1997, 35:41-47.
• [77]Esser MT, Bess JW Jr, Suryanarayana K, Chertova E, Marti D, Carrington M, Arthur LO, Lifson JD: Partial activation and induction of apoptosis in CD4(+) and CD8(+) T lymphocytes by conformationally authentic noninfectious human immunodeficiency virus type 1. J Virol 2001, 75:1152-1164.
• [78]Berndt C, Mopps B, Angermuller S, Gierschik P, Krammer PH: CXCR4 and CD4 mediate a rapid CD95-independent cell death in CD4(+) T cells. Proc Natl Acad Sci USA 1998, 95:12556-12561.
• [79]Estaquier J, Lelievre JD, Petit F, Brunner T, Moutouh-De Parseval L, Richman DD, Ameisen JC, Corbeil J: Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death. J Virol 2002, 76:5966-5973.
• [80]Lelievre JD, Mammano F, Arnoult D, Petit F, Grodet A, Estaquier J, Ameisen JC: A novel mechanism for HIV1-mediated bystander CD4+ T-cell death: neighboring dying cells drive the capacity of HIV1 to kill noncycling primary CD4+ T cells. Cell Death Differ 2004, 11:1017-1027.