HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.
References
[1]
Wherry EJ (2011) T cell exhaustion. Nat Immunol 12: 492–499. pmid:21739672 doi: 10.1038/ni.2035
[2]
Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, et al. (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443: 350–354. pmid:16921384 doi: 10.1038/nature05115
[3]
Dyavar Shetty R, Velu V, Titanji K, Bosinger SE, Freeman GJ, et al. (2012) PD-1 blockade during chronic SIV infection reduces hyperimmune activation and microbial translocation in rhesus macaques. J Clin Invest 122: 1712–1716. doi: 10.1172/JCI60612. pmid:22523065
[4]
Petrovas C, Price DA, Mattapallil J, Ambrozak DR, Geldmacher C, et al. (2007) SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 110: 928–936. pmid:17440051 doi: 10.1182/blood-2007-01-069112
[5]
Porichis F, Kaufmann DE (2012) Role of PD-1 in HIV pathogenesis and as target for therapy. Curr HIV/AIDS Rep 9: 81–90. doi: 10.1007/s11904-011-0106-4. pmid:22198819
[6]
Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, et al. (2006) Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12: 1198–1202. pmid:16917489 doi: 10.1038/nm1482
[7]
Velu V, Titanji K, Zhu B, Husain S, Pladevega A, et al. (2009) Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458: 206–210. doi: 10.1038/nature07662. pmid:19078956
[8]
Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, et al. (2008) Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med 205: 2763–2779. doi: 10.1084/jem.20081398. pmid:19001139
[9]
Vali B, Jones RB, Sakhdari A, Sheth PM, Clayton K, et al. (2010) HCV-specific T cells in HCV/HIV co-infection show elevated frequencies of dual Tim-3/PD-1 expression that correlate with liver disease progression. Eur J Immunol 40: 2493–2505. doi: 10.1002/eji.201040340. pmid:20623550
[10]
Kaufmann DE, Walker BD (2009) PD-1 and CTLA-4 inhibitory cosignaling pathways in HIV infection and the potential for therapeutic intervention. J Immunol 182: 5891–5897. doi: 10.4049/jimmunol.0803771. pmid:19414738
[11]
Vigano S, Banga R, Bellanger F, Pellaton C, Farina A, et al. (2014) CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression. PLoS Pathog 10: e1004380. doi: 10.1371/journal.ppat.1004380. pmid:25255144
[12]
Tian X, Zhang A, Qiu C, Wang W, Yang Y, et al. (2015) The Upregulation of LAG-3 on T Cells Defines a Subpopulation with Functional Exhaustion and Correlates with Disease Progression in HIV-Infected Subjects. J Immunol 194: 3873–3882. doi: 10.4049/jimmunol.1402176. pmid:25780040
[13]
Gardiner D, Lalezari J, Lawitz E, DiMicco M, Ghalib R, et al. (2013) A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One 8: e63818. doi: 10.1371/journal.pone.0063818. pmid:23717490
[14]
Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, et al. (2014) Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515: 572–576. doi: 10.1038/nature14001. pmid:25428506
[15]
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, et al. (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515: 558–562. doi: 10.1038/nature13904. pmid:25428503
[16]
Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, et al. (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369: 134–144. doi: 10.1056/NEJMoa1305133. pmid:23724846
[17]
Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39: 1–10. doi: 10.1016/j.immuni.2013.07.012. pmid:23890059
[18]
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, et al. (2014) The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell 26: 923–937. doi: 10.1016/j.ccell.2014.10.018. pmid:25465800
[19]
Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang H, et al. (2015) TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients. J Clin Invest. doi: 10.1172/jci80445
[20]
Yamamoto T, Price DA, Casazza JP, Ferrari G, Nason M, et al. (2011) Surface expression patterns of negative regulatory molecules identify determinants of virus-specific CD8+ T-cell exhaustion in HIV infection. Blood 117: 4805–4815. doi: 10.1182/blood-2010-11-317297. pmid:21398582
[21]
Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 73: 3591–3603. doi: 10.1158/0008-5472.CAN-12-4100. pmid:23633484
[22]
Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, et al. (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10: 29–37. doi: 10.1038/ni.1679. pmid:19043418
[23]
Yu X, Harden K, Gonzalez LC, Francesco M, Chiang E, et al. (2009) The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells. Nat Immunol 10: 48–57. doi: 10.1038/ni.1674. pmid:19011627
[24]
Stengel KF, Harden-Bowles K, Yu X, Rouge L, Yin J, et al. (2012) Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci U S A 109: 5399–5404. doi: 10.1073/pnas.1120606109. pmid:22421438
[25]
Joller N, Hafler JP, Brynedal B, Kassam N, Spoerl S, et al. (2011) Cutting edge: TIGIT has T cell-intrinsic inhibitory functions. J Immunol 186: 1338–1342. doi: 10.4049/jimmunol.1003081. pmid:21199897
[26]
Stanietsky N, Simic H, Arapovic J, Toporik A, Levy O, et al. (2009) The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U S A 106: 17858–17863. doi: 10.1073/pnas.0903474106. pmid:19815499
[27]
Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, et al. (2009) A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol 39: 695–703. doi: 10.1002/eji.200839116. pmid:19197944
Foks AC, Ran IA, Frodermann V, Bot I, van Santbrink PJ, et al. (2013) Agonistic anti-TIGIT treatment inhibits T cell responses in LDLr deficient mice without affecting atherosclerotic lesion development. PLoS One 8: e83134. doi: 10.1371/journal.pone.0083134. pmid:24376654
[30]
Joller N, Lozano E, Burkett PR, Patel B, Xiao S, et al. (2014) Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity 40: 569–581. doi: 10.1016/j.immuni.2014.02.012. pmid:24745333
[31]
Lozano E, Dominguez-Villar M, Kuchroo V, Hafler DA (2012) The TIGIT/CD226 axis regulates human T cell function. J Immunol 188: 3869–3875. doi: 10.4049/jimmunol.1103627. pmid:22427644
[32]
Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, et al. (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8: 379–385. pmid:11927944 doi: 10.1038/nm0402-379
[33]
Papagno L, Spina CA, Marchant A, Salio M, Rufer N, et al. (2004) Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol 2: E20. pmid:14966528 doi: 10.1371/journal.pbio.0020020
[34]
Barbour JD, Ndhlovu LC, Xuan Tan Q, Ho T, Epling L, et al. (2009) High CD8+ T cell activation marks a less differentiated HIV-1 specific CD8+ T cell response that is not altered by suppression of viral replication. PLoS One 4: e4408. doi: 10.1371/journal.pone.0004408. pmid:19198651
[35]
Mujib S, Jones RB, Lo C, Aidarus N, Clayton K, et al. (2012) Antigen-independent induction of Tim-3 expression on human T cells by the common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 is associated with proliferation and is dependent on the phosphoinositide 3-kinase pathway. J Immunol 188: 3745–3756. doi: 10.4049/jimmunol.1102609. pmid:22422881
[36]
Sun Y, Schmitz JE, Acierno PM, Santra S, Subbramanian RA, et al. (2005) Dysfunction of simian immunodeficiency virus/simian human immunodeficiency virus-induced IL-2 expression by central memory CD4+ T lymphocytes. J Immunol 174: 4753–4760. pmid:15814700 doi: 10.4049/jimmunol.174.8.4753
[37]
Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, et al. (2003) HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med 198: 1909–1922. pmid:14676302 doi: 10.1084/jem.20031598
[38]
Fujita T, Burwitz BJ, Chew GM, Reed JS, Pathak R, et al. (2014) Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques. J Immunol 193: 5576–5583. doi: 10.4049/jimmunol.1400961. pmid:25348621
[39]
Hosking MP, Flynn CT, Botten J, Whitton JL (2013) CD8+ memory T cells appear exhausted within hours of acute virus infection. J Immunol 191: 4211–4222. doi: 10.4049/jimmunol.1300920. pmid:24026080
[40]
Rekik R, Belhadj Hmida N, Ben Hmid A, Zamali I, Kammoun N, et al. (2014) PD-1 induction through TCR activation is partially regulated by endogenous TGF-beta. Cell Mol Immunol. doi: 10.1038/cmi.2014.104
[41]
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, et al. (2008) The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 181: 6738–6746. pmid:18981091 doi: 10.4049/jimmunol.181.10.6738
[42]
Lambotte O, Boufassa F, Madec Y, Nguyen A, Goujard C, et al. (2005) HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous control of viral replication. Clin Infect Dis 41: 1053–1056. pmid:16142675 doi: 10.1086/433188
[43]
Krishnan S, Wilson EM, Sheikh V, Rupert A, Mendoza D, et al. (2014) Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis 209: 931–939. doi: 10.1093/infdis/jit581. pmid:24185941
[44]
Okulicz JF, Lambotte O (2011) Epidemiology and clinical characteristics of elite controllers. Curr Opin HIV AIDS 6: 163–168. doi: 10.1097/COH.0b013e328344f35e. pmid:21502920
[45]
Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, et al. (2008) Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197: 126–133. doi: 10.1086/524143. pmid:18171295
[46]
Lopez M, Soriano V, Peris-Pertusa A, Rallon N, Restrepo C, et al. (2011) Elite controllers display higher activation on central memory CD8 T cells than HIV patients successfully on HAART. AIDS Res Hum Retroviruses 27: 157–165. doi: 10.1089/aid.2010.0107. pmid:20964478
[47]
Pereyra F, Palmer S, Miura T, Block BL, Wiegand A, et al. (2009) Persistent low-level viremia in HIV-1 elite controllers and relationship to immunologic parameters. J Infect Dis 200: 984–990. doi: 10.1086/605446. pmid:19656066
[48]
Hatano H, Delwart EL, Norris PJ, Lee TH, Dunn-Williams J, et al. (2009) Evidence for persistent low-level viremia in individuals who control human immunodeficiency virus in the absence of antiretroviral therapy. J Virol 83: 329–335. doi: 10.1128/JVI.01763-08. pmid:18945778
[49]
Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, et al. (2014) Hospitalization Rates and Reasons among HIV Elite Controllers and Persons With Medically Controlled HIV Infection. J Infect Dis. doi: 10.1093/infdis/jiu809
[50]
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366: 2443–2454. doi: 10.1056/NEJMoa1200690. pmid:22658127
[51]
Pasternak AO, Lukashov VV, Berkhout B (2013) Cell-associated HIV RNA: a dynamic biomarker of viral persistence. Retrovirology 10: 41. doi: 10.1186/1742-4690-10-41. pmid:23587031
[52]
Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, et al. (2012) Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature 487: 482–485. doi: 10.1038/nature11286. pmid:22837004
[53]
Wei DG, Chiang V, Fyne E, Balakrishnan M, Barnes T, et al. (2014) Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. PLoS Pathog 10: e1004071. doi: 10.1371/journal.ppat.1004071. pmid:24722454
[54]
Rasmussen TA, Schmeltz Sogaard O, Brinkmann C, Wightman F, Lewin SR, et al. (2013) Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. Hum Vaccin Immunother 9: 993–1001. doi: 10.4161/hv.23800. pmid:23370291
[55]
Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, et al. (2012) Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity 36: 491–501. doi: 10.1016/j.immuni.2012.01.014. pmid:22406268
[56]
Deng K, Pertea M, Rongvaux A, Wang L, Durand CM, et al. (2015) Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations. Nature 517: 381–385. doi: 10.1038/nature14053. pmid:25561180
Clayton KL, Douglas-Vail MB, Rahman AK, Medcalf KE, Xie IY, et al. (2015) Soluble T Cell Immunoglobulin Mucin Domain 3 Is Shed from CD8+ T Cells by the Sheddase ADAM10, Is Increased in Plasma during Untreated HIV Infection, and Correlates with HIV Disease Progression. J Virol 89: 3723–3736. doi: 10.1128/JVI.00006-15. pmid:25609823
[59]
Watters MR, Poff PW, Shiramizu BT, Holck PS, Fast KM, et al. (2004) Symptomatic distal sensory polyneuropathy in HIV after age 50. Neurology 62: 1378–1383. pmid:15111677 doi: 10.1212/01.wnl.0000120622.91018.ea
[60]
Kumar AM, Borodowsky I, Fernandez B, Gonzalez L, Kumar M (2007) Human immunodeficiency virus type 1 RNA Levels in different regions of human brain: quantification using real-time reverse transcriptase-polymerase chain reaction. J Neurovirol 13: 210–224. pmid:17613711 doi: 10.1080/13550280701327038
[61]
Lonberg N, Taylor LD, Harding FA, Trounstine M, Higgins KM, et al. (1994) Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368: 856–859. pmid:8159246 doi: 10.1038/368856a0
[62]
Fishwild DM, O'Donnell SL, Bengoechea T, Hudson DV, Harding F, et al. (1996) High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Biotechnol 14: 845–851. pmid:9631008 doi: 10.1038/nbt0796-845
[63]
Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, et al. (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. impaired B cell maturation in mice lacking BLyS. Immunity 15: 289–302. pmid:11520463 doi: 10.1016/s1074-7613(01)00183-2
