The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts. Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells. Knockdown of Bak by RNA interference inhibited CD95/Fas-induced death of T cells from HIV-1-infected individuals. In HIV-1-infected patients, IFNα-stimulated gene expression correlated positively with ex vivo T cell Bak levels, CD95/Fas-mediated apoptosis and viremia and negatively with CD4+ T cell counts. In vitro IFNα/β stimulation enhanced Bak expression, CD95/Fas expression and CD95/Fas-mediated apoptosis in healthy donor T cells and induced death of HIV-specific CD8+ T cells from HIV-1-infected patients. HIV-1 in vitro sensitized T cells to CD95/Fas-induced apoptosis and this was Toll-like receptor (TLR)7/9- and Type I IFN-dependent. This sensitization by HIV-1 was due to an indirect effect on T cells, as it occurred in peripheral blood mononuclear cell cultures but not purified CD4+ T cells. Finally, peak IFNα levels and viral loads correlated negatively during acute SIV infection suggesting a potential antiviral effect, but positively during chronic SIV infection indicating that either the virus drives IFNα production or IFNα may facilitate loss of viral control. The above findings indicate stage-specific opposing effects of Type I IFNs during HIV-1 infection and suggest a novel mechanism by which these cytokines contribute to T cell depletion, dysregulation of cellular immunity and disease progression.
References
[1]
Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, et al. (1995) Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1: 129–134. doi: 10.1038/nm0295-129
[2]
Gougeon ML, Garcia S, Heeney J, Tschopp R, Lecoeur H, et al. (1993) Programmed cell death in AIDS-related HIV and SIV infections. AIDS Res Hum Retroviruses 9: 553–563. doi: 10.1089/aid.1993.9.553
[3]
Meyaard L, Otto SA, Jonker RR, Mijnster MJ, Keet RP, et al. (1992) Programmed death of T cells in HIV-1 infection. Science 257: 217–219. doi: 10.1126/science.1352911
[4]
Gougeon ML, Lecoeur H, Dulioust A, Enouf MG, Crouvoiser M, et al. (1996) Programmed cell death in peripheral lymphocytes from HIV-infected persons: increased susceptibility to apoptosis of CD4 and CD8 T cells correlates with lymphocyte activation and with disease progression. J Immunol 156: 3509–3520.
[5]
Katsikis PD, Wunderlich ES, Smith CA, Herzenberg LA (1995) Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 181: 2029–2036. doi: 10.1084/jem.181.6.2029
[6]
Estaquier J, Idziorek T, Zou W, Emilie D, Farber CM, et al. (1995) 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 182: 1759–1767. doi: 10.1084/jem.182.6.1759
[7]
Mueller YM, De Rosa SC, Hutton JA, Witek J, Roederer M, et al. (2001) Increased CD95/Fas-induced apoptosis of HIV-specific CD8(+) T cells. Immunity 15: 871–882. doi: 10.1016/s1074-7613(01)00246-1
[8]
Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, et al. (1999) Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179: 859–870. doi: 10.1086/314660
[9]
Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, et al. (2008) Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 14: 1077–1087. doi: 10.1038/nm.1871
[10]
von Sydow M, Sonnerborg A, Gaines H, Strannegard O (1991) Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses 7: 375–380. doi: 10.1089/aid.1991.7.375
[11]
Piasecki E, Knysz B, Gasiorowski J, Gladysz A (1999) Decrease of enhanced interferon alpha levels in sera of HIV-infected and AIDS patients receiving combined antiretroviral therapy. Arch Immunol Ther Exp (Warsz) 47: 37–44.
[12]
Swindells S, Baldwin T, Kelly C, Baca-Regen L, Loomis L, et al. (1996) Regulation and characterization of the interferon-alpha present in patients with advanced human immunodeficiency virus type 1 disease. J Interferon Cytokine Res 16: 127–137. doi: 10.1089/jir.1996.16.127
[13]
Meylan PR, Guatelli JC, Munis JR, Richman DD, Kornbluth RS (1993) Mechanisms for the inhibition of HIV replication by interferons-alpha, -beta, and -gamma in primary human macrophages. Virology 193: 138–148. doi: 10.1006/viro.1993.1110
[14]
Cheney KM, McKnight A (2010) Interferon-alpha mediates restriction of human immunodeficiency virus type-1 replication in primary human macrophages at an early stage of replication. PLoS One 5: e13521. doi: 10.1371/journal.pone.0013521
[15]
Luft T, Pang KC, Thomas E, Hertzog P, Hart DN, et al. (1998) Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol 161: 1947–1953.
[16]
Dondi E, Roue G, Yuste VJ, Susin SA, Pellegrini S (2004) A dual role of IFN-alpha in the balance between proliferation and death of human CD4+ T lymphocytes during primary response. J Immunol 173: 3740–3747. doi: 10.4049/jimmunol.173.6.3740
[17]
Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, et al. (2003) Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 17: 1881–1888. doi: 10.1097/00002030-200309050-00006
[18]
Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, et al. (2004) Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load. Blood 104: 942–947. doi: 10.1182/blood-2003-09-3333
[19]
Audige A, Urosevic M, Schlaepfer E, Walker R, Powell D, et al. (2006) Anti-HIV state but not apoptosis depends on IFN signature in CD4+ T cells. J Immunol 177: 6227–6237. doi: 10.4049/jimmunol.177.9.6227
[20]
Lane HC, Davey V, Kovacs JA, Feinberg J, Metcalf JA, et al. (1990) Interferon-alpha in patients with asymptomatic human immunodeficiency virus (HIV) infection. A randomized, placebo-controlled trial. Ann Intern Med 112: 805–811. doi: 10.7326/0003-4819-112-11-805
[21]
Asmuth DM, Murphy RL, Rosenkranz SL, Lertora JJ, Kottilil S, et al. (2010) Safety, tolerability, and mechanisms of antiretroviral activity of pegylated interferon Alfa-2a in HIV-1-monoinfected participants: a phase II clinical trial. J Infect Dis 201: 1686–1696. doi: 10.1086/652420
[22]
Kovacs JA, Bechtel C, Davey RT Jr, Falloon J, Polis MA, et al. (1996) Combination therapy with didanosine and interferon-alpha in human immunodeficiency virus-infected patients: results of a phase I/II trial. J Infect Dis 173: 840–848. doi: 10.1093/infdis/173.4.840
[23]
Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D, et al. (2009) Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 119: 3544–3555. doi: 10.1172/jci40093
[24]
Keir ME, Rosenberg MG, Sandberg JK, Jordan KA, Wiznia A, et al. (2002) Generation of CD3+CD8low thymocytes in the HIV type 1-infected thymus. J Immunol 169: 2788–2796. doi: 10.4049/jimmunol.169.5.2788
[25]
Herbeuval JP, Nilsson J, Boasso A, Hardy AW, Kruhlak MJ, et al. (2006) Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci U S A 103: 7000–7005. doi: 10.1073/pnas.0600363103
[26]
Fernandez S, Tanaskovic S, Helbig K, Rajasuriar R, Kramski M, et al. (2011) CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J Infect Dis 204: 1927–1935. doi: 10.1093/infdis/jir659
[27]
Baumler CB, Bohler T, Herr I, Benner A, Krammer PH, et al. (1996) Activation of the CD95 (APO-1/Fas) system in T cells from human immunodeficiency virus type-1-infected children. Blood 88: 1741–1746.
[28]
Boudet F, Lecoeur H, Gougeon ML (1996) Apoptosis associated with ex vivo down-regulation of Bcl-2 and up-regulation of Fas in potential cytotoxic CD8+ T lymphocytes during HIV infection. J Immunol 156: 2282–2293.
[29]
Badley AD, Dockrell D, Simpson M, Schut R, Lynch DH, et al. (1997) Macrophage-dependent apoptosis of CD4+ T lymphocytes from HIV-infected individuals is mediated by FasL and tumor necrosis factor. J Exp Med 185: 55–64. doi: 10.1084/jem.185.1.55
[30]
Petrovas C, Mueller YM, Dimitriou ID, Bojczuk PM, Mounzer KC, et al. (2004) HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. J Immunol 172: 4444–4453. doi: 10.4049/jimmunol.172.7.4444
[31]
Arnoult D, Petit F, Lelievre JD, Lecossier D, Hance A, et al. (2003) Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression. Cell Death Differ 10: 1240–1252. doi: 10.1038/sj.cdd.4401289
[32]
David D, Keller H, Nait-Ighil L, Treilhou MP, Joussemet M, et al. (2002) Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy. AIDS 16: 1093–1101. doi: 10.1097/00002030-200205240-00002
[33]
Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA (1995) CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest 95: 2061–2066. doi: 10.1172/jci117892
[34]
Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, et al. (2005) Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 115: 3265–3275. doi: 10.1172/jci26032
[35]
Meier A, Alter G, Frahm N, Sidhu H, Li B, et al. (2007) MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol 81: 8180–8191. doi: 10.1128/jvi.00421-07
[36]
Hosmalin A, Lebon P (2006) Type I interferon production in HIV-infected patients. J Leukoc Biol 80: 984–993. doi: 10.1189/jlb.0306154
[37]
Gorden KK, Qiu X, Battiste JJ, Wightman PP, Vasilakos JP, et al. (2006) Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines. J Immunol 177: 8164–8170. doi: 10.4049/jimmunol.177.11.8164
[38]
Haas T, Metzger J, Schmitz F, Heit A, Muller T, et al. (2008) The DNA sugar backbone 2′ deoxyribose determines toll-like receptor 9 activation. Immunity 28: 315–323. doi: 10.1016/j.immuni.2008.01.013
[39]
Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS (2006) Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 177: 6584–6587. doi: 10.4049/jimmunol.177.10.6584
[40]
Fauci AS, Pantaleo G, Stanley S, Weissman D (1996) Immunopathogenic mechanisms of HIV infection. Ann Intern Med 124: 654–663. doi: 10.7326/0003-4819-124-7-199604010-00006
[41]
Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE (2002) CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause? Nat Med 8: 319–323. doi: 10.1038/nm0402-319
[42]
Gehri R, Hahn S, Rothen M, Steuerwald M, Nuesch R, et al. (1996) The Fas receptor in HIV infection: expression on peripheral blood lymphocytes and role in the depletion of T cells. AIDS 10: 9–16. doi: 10.1097/00002030-199601000-00002
[43]
Salvato MS, Yin CC, Yagita H, Maeda T, Okumura K, et al. (2007) Attenuated disease in SIV-infected macaques treated with a monoclonal antibody against FasL. Clin Dev Immunol 2007: 93462. doi: 10.1155/2007/93462
[44]
Jeremias I, Herr I, Boehler T, Debatin KM (1998) TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur J Immunol 28: 143–152. doi: 10.1002/(sici)1521-4141(199801)28:01<143::aid-immu143>3.0.co;2-3
[45]
Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C, et al. (2005) CD4+ T-cell death induced by infectious and noninfectious HIV-1: role of type 1 interferon-dependent, TRAIL/DR5-mediated apoptosis. Blood 106: 3524–3531. doi: 10.1182/blood-2005-03-1243
[46]
Miura Y, Misawa N, Maeda N, Inagaki Y, Tanaka Y, et al. (2001) Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4+ T cells in HIV-1-infected hu-PBL-NOD-SCID mice. J Exp Med 193: 651–660. doi: 10.1084/jem.193.5.651
[47]
Katsikis PD, Garcia-Ojeda ME, Torres-Roca JF, Tijoe IM, Smith CA, et al. (1997) Interleukin-1 beta converting enzyme-like protease involvement in Fas-induced and activation-induced peripheral blood T cell apoptosis in HIV infection. TNF-related apoptosis-inducing ligand can mediate activation-induced T cell death in HIV infection. J Exp Med 186: 1365–1372. doi: 10.1084/jem.186.8.1365
[48]
de Oliveira Pinto LM, Garcia S, Lecoeur H, Rapp C, Gougeon ML (2002) Increased sensitivity of T lymphocytes to tumor necrosis factor receptor 1 (TNFR1)- and TNFR2-mediated apoptosis in HIV infection: relation to expression of Bcl-2 and active caspase-8 and caspase-3. Blood 99: 1666–1675. doi: 10.1182/blood.v99.5.1666
[49]
Herbein G, Van Lint C, Lovett JL, Verdin E (1998) Distinct mechanisms trigger apoptosis in human immunodeficiency virus type 1-infected and in uninfected bystander T lymphocytes. J Virol 72: 660–670.
[50]
Shepard BD, De Forni D, McNamara DR, Foli A, Rizza SA, et al. (2008) Beneficial effect of TRAIL on HIV burden, without detectable immune consequences. PLoS One 3: e3096. doi: 10.1371/journal.pone.0003096
[51]
Chehimi J, Papasavvas E, Tomescu C, Gekonge B, Abdulhaqq S, et al. (2010) 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 84: 2762–2773. doi: 10.1128/jvi.01350-09
[52]
Thomas WD, Hersey P (1998) TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in Fas ligand-resistant melanoma cells and mediates CD4 T cell killing of target cells. J Immunol 161: 2195–2200.
[53]
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, et al. (1997) Inhibition of death receptor signals by cellular FLIP. Nature 388: 190–195. doi: 10.1038/40657
[54]
Han J, Goldstein LA, Gastman BR, Rabinovitz A, Wang GQ, et al. (2004) Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells. Leukemia 18: 1671–1680. doi: 10.1038/sj.leu.2403496
[55]
McCloskey TW, Bakshi S, Than S, Arman P, Pahwa S (1998) Immunophenotypic analysis of peripheral blood mononuclear cells undergoing in vitro apoptosis after isolation from human immunodeficiency virus-infected children. Blood 92: 4230–4237.
[56]
Lavrik IN, Krammer PH (2012) Regulation of CD95/Fas signaling at the DISC. Cell Death Differ 19: 36–41. doi: 10.1038/cdd.2011.155
[57]
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, et al. (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292: 727–730. doi: 10.1126/science.1059108
[58]
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, et al. (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14: 2060–2071.
[59]
Petrovas C, Mueller YM, Dimitriou ID, Altork SR, Banerjee A, et al. (2007) Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8(+) T cells. Blood 109: 2505–2513. doi: 10.1182/blood-2006-05-021626
[60]
Petrovas C, Mueller YM, Katsikis PD (2005) Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy. Cell Death Differ 12 Suppl 1: 859–870. doi: 10.1038/sj.cdd.4401595
[61]
Viollet L, Monceaux V, Petit F, Ho Tsong Fang R, Cumont MC, et al. (2006) Death of CD4+ T cells from lymph nodes during primary SIVmac251 infection predicts the rate of AIDS progression. J Immunol 177: 6685–6694. doi: 10.4049/jimmunol.177.10.6685
[62]
Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, et al. (2011) IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 186: 2772–2779. doi: 10.4049/jimmunol.1003208
[63]
Lederer S, Favre D, Walters KA, Proll S, Kanwar B, et al. (2009) Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 5: e1000296. doi: 10.1371/journal.ppat.1000296
[64]
Estaquier J, Idziorek T, de Bels F, Barre-Sinoussi F, Hurtrel B, et al. (1994) Programmed cell death and AIDS: significance of T-cell apoptosis in pathogenic and nonpathogenic primate lentiviral infections. Proc Natl Acad Sci U S A 91: 9431–9435. doi: 10.1073/pnas.91.20.9431
[65]
Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, et al. (2003) Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18: 441–452. doi: 10.1016/s1074-7613(03)00060-8
[66]
Malleret B, Maneglier B, Karlsson I, Lebon P, Nascimbeni M, et al. (2008) Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression. Blood 112: 4598–4608. doi: 10.1182/blood-2008-06-162651
[67]
Teijaro JR, Ng C, Lee AM, Sullivan BM, Sheehan KC, et al. (2013) Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 340: 207–211. doi: 10.1126/science.1235214
[68]
Wilson EB, Yamada DH, Elsaesser H, Herskovitz J, Deng J, et al. (2013) Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 340: 202–207. doi: 10.1126/science.1235208
[69]
Odorizzi PM, Wherry EJ (2013) Immunology. An interferon paradox. Science 340: 155–156. doi: 10.1126/science.1237568
[70]
Parker R, Dutrieux J, Beq S, Lemercier B, Rozlan S, et al. (2010) Interleukin-7 treatment counteracts IFN-alpha therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques. Blood 116: 5589–5599. doi: 10.1182/blood-2010-03-276261
[71]
Vanderford TH, Slichter C, Rogers KA, Lawson BO, Obaede R, et al. (2012) Treatment of SIV-infected sooty mangabeys with a type-I IFN agonist results in decreased virus replication without inducing hyperimmune activation. Blood 119: 5750–5757. doi: 10.1182/blood-2012-02-411496
[72]
Baum P, Fundel-Clemens K, Kreuz S, Kontermann RE, Weith A, et al. (2010) Off-target analysis of control siRNA molecules reveals important differences in the cytokine profile and inflammation response of human fibroblasts. Oligonucleotides 20: 17–26. doi: 10.1089/oli.2009.0213
[73]
Lu W, Andrieu JM (2001) In vitro human immunodeficiency virus eradication by autologous CD8(+) T cells expanded with inactivated-virus-pulsed dendritic cells. J Virol 75: 8949–8956. doi: 10.1128/jvi.75.19.8949-8956.2001
[74]
Fraietta JA, Mueller YM, Do DH, Holmes VM, Howett MK, et al. (2010) Phosphorothioate 2′ deoxyribose oligomers as microbicides that inhibit human immunodeficiency virus type 1 (HIV-1) infection and block Toll-like receptor 7 (TLR7) and TLR9 triggering by HIV-1. Antimicrob Agents Chemother 54: 4064–4073. doi: 10.1128/aac.00367-10
[75]
Helbig KJ, Lau DT, Semendric L, Harley HA, Beard MR (2005) Analysis of ISG expression in chronic hepatitis C identifies viperin as a potential antiviral effector. Hepatology 42: 702–710. doi: 10.1002/hep.20844
[76]
Giavedoni LD (2005) Simultaneous detection of multiple cytokines and chemokines from nonhuman primates using luminex technology. J Immunol Methods 301: 89–101. doi: 10.1016/j.jim.2005.03.015
