Eradication of HIV infection will require the identification of all cellular reservoirs that harbor latent infection. Despite low or lack of CD4 receptor expression on Vδ2 T cells, infection of these cells has previously been reported. We found that upregulation of the CD4 receptor may render primary Vδ2 cells target for HIV infection in vitro and we propose that HIV-induced immune activation may allow infection of γδ T cells in vivo. We assessed the presence of latent HIV infection by measurements of DNA and outgrowth assays within Vδ2 cells in 18 aviremic patients on long-standing antiretroviral therapy. In 14 patients we recovered latent but replication-competent HIV from highly purified Vδ2 cells demonstrating that peripheral Vδ2 T cells are a previously unrecognized reservoir in which latent HIV infection is unexpectedly frequent.
References
[1]
Stevenson M, Stanwick TL, Dempsey MP, Lamonica CA. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 1990; 9: 1551–1560. pmid:2184033
[2]
Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997; 387: 183–188. pmid:9144289 doi: 10.1038/387183a0
[3]
Finzi D, Blankson J, Siliciano JD, Margolisk JD, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999; 5: 512–517. pmid:10229227
[4]
Wong J, Hezareh M, Günthard HF, Havlir DV, Ignacio CC, Richman DD. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia Science 1997; 278: 1291–1294. pmid:9360926 doi: 10.1126/science.278.5341.1291
[5]
Siliciano JD, Kajdas J, Finzi D, Quinn TC, Margolick JB, Kovacs C, et al. Longterm follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003; 9: 727–728. pmid:12754504 doi: 10.1038/nm880
[6]
Hayday AC. gammadelta cells: a right time and a right place for a conserved third way of protection Annu Rev Immunol. 2000; 18: 975–1026. pmid:10837080 doi: 10.1146/annurev.immunol.18.1.975
[7]
Tanaka Y, Sano S, Nieves E, De Libero G, Rosa D, Modlin , et al. Nonpeptide ligands for human gamma delta T cells Proc Natl Acad Sci USA 1994; 91: 8175–8179. pmid:8058775 doi: 10.1073/pnas.91.17.8175
[8]
Hintz M, Reichenberg A, Altincicek B, Bahr U., Gschwind RM, Kollas AK et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human gammadelta T cells in Escherichia coli. 2001; FEBS Lett. 509: 317–322. pmid:11741609 doi: 10.1016/s0014-5793(01)03191-x
[9]
Jomaa H, Wiesner J, Sanderbrand S, Altincicek B, Weidemeyer C, Hintz M, et al. Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs Science 1999; 285: 1573–1576. pmid:10477522 doi: 10.1126/science.285.5433.1573
[10]
Tanaka Y, Morita CT, Nieves E, Brenner MB, Bloom BR. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells Nature 1995; 375: 155–158. pmid:7753173 doi: 10.1038/375155a0
[11]
Miyawaki T, Kasahara Y, Taga K, Yachie A, Taniguchi N. Differential expression of CD45RO (UCHL1) and its functional relevance in two subpopulations of circulating TCR-gamma/delta+ lymphocytes J Exp Med. 1990; 171: 1833–1838. pmid:2139700 doi: 10.1084/jem.171.5.1833
[12]
Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C, et al. Differentiation of effector/memory Vδ2 T cells and migratory routes in lymph nodes or inflammatory sites J Exp Med. 2003; 198: 391–397. pmid:12900516 doi: 10.1084/jem.20030235
[13]
Cummings JS, Cairo C, Armstrong C, Davis C, Pauza CD. Impacts of HIV infection on Vγ2Vδ2 T cell phenotype and function: a mechanism for reduced tumor immunity in AIDS J Leuk Biol. 2008; 84: 371–379 doi: 10.1189/jlb.1207847
[14]
Autran B, Triebel F, Katlama C, Rozenbaum W, Debre P. T cell receptor gamma/delta+ lymphocyte subsets during HIV infection Clin Exp Immunol. 1989; 75: 206–210. pmid:2522839
[15]
Poccia F, Boullier S, Lecoeur H, Cochet M, Poquet Y, Colizzi V et al. Peripheral Vg9/Vd2 T cell deletion and anergy to nonpeptidic mycobacterial antigens in asymptomatic HIV-1-infected persons J Immunol. 1996; 157: 449–461. pmid:8683151
[16]
Li H, Pauza CD. HIV envelope-mediated, CCR5/alpha4beta7-dependent killing of CD4-negative gammadelta T cells, which are lost during progression to AIDS. Blood 2011; 118: 5824–5831. doi: 10.1182/blood-2011-05-356535. pmid:21926353
[17]
Imlach S, Leen C, Bell JE, Simmonds P. Phenotypic analysis of peripheral blood γδ T lymphocytes and their targeting by Human Immunodeficiency virus type 1 in vivo Virology 2003; 305: 415–427. pmid:12573587 doi: 10.1006/viro.2002.1759
[18]
Wallace M, Scharko AM, Pauza CD, Fisch P, Imaoka K, Kawabata S et al. Functional γδ T-lymphocyte defect associated with human immunodeficiency virus infections Mol Med. 1997; 3: 60–71. pmid:9132281
Siliciano JD, Siliciano RF. Enhanced culture assay for detection and quantification of latently, resting CD4+ T cells carrying replication-competent virus in HIV-1-infected individuals Methods Mol Biol. 2005; 304: 3–15. pmid:16061962 doi: 10.1385/1-59259-907-9:003
[21]
Archin NM, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA, Wiegand A et al. Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells AIDS 2008; 22: 1131–1135. doi: 10.1097/QAD.0b013e3282fd6df4. pmid:18525258
[22]
Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, et al. Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies PLoS Pathog. 2013; 9(2):e1003174. doi: 10.1371/journal.ppat.1003174. pmid:23459007
[23]
Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, Archin NM. Quantitation of replication-competent HIV-1 in populations of resting-CD4+ cells. J Virol. 2014 88:14070–14077. doi: 10.1128/JVI.01900-14. pmid:25253353
[24]
Crooks AM, Bateson R, Cope AB, Dahl NP, Griggs MK, Kuruc JD, Gay CL, Eron JJ, Margolis DM, Bosch RJ, Archin NM. Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies. J Infect Dis. 2015; ahead of print. doi: 10.1093/infdis/jiv218
[25]
Wallace M, Bartz SR, Chang W-L, Mackenzie D, Pauza CD, Malkovsky M. Gamma delta T lymphocyte responses to human immunodeficiency virus Clin Exp Immunol. 1996; 103: 177–184. pmid:8565297 doi: 10.1046/j.1365-2249.1996.d01-625.x
[26]
Poccia F, Battistini L, Cipriani B, Mancino G, Martini F, Gougeon ML, et al. Phosphoantigen-reactive Vgamma9Vdelta2 T lymphocytes suppress in vitro human immunodeficiency virus type 1 replication by cell-released antiviral factors including CC chemokines. J Infect Dis. 1990; 180: 858–861. doi: 10.1086/314925
[27]
Bordon J, Evans PS, Propp N, Davis CE Jr, Redfield RR, Pauza CD. Association between longer duration of HIV-suppressive therapy and partial recovery of the Vg2 T cell receptor repertoire. J Infect Dis. 2004; 189: 1482–1486. pmid:15073686 doi: 10.1086/382961
[28]
Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002; 418: 646–650. pmid:12167863 doi: 10.1038/nature00939
[29]
Henriet S, Mercenne G, Bernacchi S, Paillart JC, Marquet R. Tumultuous relationship between the human immunodeficiency virus type 1 viral infectivity factor (Vif) and the human APOBEC-3G and APOBEC-3F restriction factors. Microbiol Mol Biol Rev. 2009; 73: 211–232. doi: 10.1128/MMBR.00040-08. pmid:19487726
[30]
Yukl SA, Sinclair E, Somsouk M, Hunt PW, Epling L, Killian M, et al. A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+T cells, including myeloid cells. AIDS 2013; 27: 2255–2260. doi: 10.1097/qad.0000000000000166
[31]
Lusso P, Garzino-Demo A, Crowley RW, Malnati MS. Infection of gamma/delta T lymphocytes by human herpesvirus 6: transcriptional induction of CD4 and susceptibility to HIV infection. J Exp Med. 1995; 181: 1303–1310. pmid:7699322 doi: 10.1084/jem.181.4.1303
[32]
Kabelitz D. γδ T cells: cross-talk between innate and adaptive immunity Cell Mol Life Sci. 2011; 68: 2331–2333. doi: 10.1007/s00018-011-0696-4. pmid:21541699
[33]
Ismaili J, Olislagers V, Poupot R, Fournié JJ, Goldman M. Human gamma delta T cells induce dendritic cell maturation Clin Immunol. 2002; 103: 296–302. pmid:12173304 doi: 10.1006/clim.2002.5218
[34]
Devilder MC, Maillet S, Bouyge-Moreau I, Donnadieu E, Bonneville M, Scotet E. Potentiation of antigen-stimulated V gamma 9V delta 2 T cell cytokine production by immature dendritic cells (DC) and reciprocal effect on DC maturation. J Immunol. 2006; 176: 1386–1393. pmid:16424165 doi: 10.4049/jimmunol.176.3.1386
[35]
Gruenbacher G, Gander H, Rahm A, Nussbaumer W, Romani N, Thurnher M. CD56+ human blood dendritic cells effectively promote TH1-type gammadelta T-cell responses Blood 2009; 114: 4422–4431. doi: 10.1182/blood-2009-06-227256. pmid:19762486
[36]
Devilder MC, Allain S, Dousset C, Bonneville M, Scotet E. Early triggering of exclusive IFN-gamma responses of human Vgamma9Vdelta2 T cells by TLR-activated myeloid and plasmacytoid dendritic cells. J Immunol. 2009; 183: 3625–3633. doi: 10.4049/jimmunol.0901571. pmid:19710464
[37]
Chen ZW. Immune biology of Ag-specific γδ T cells in infections Cell Mol Life Sci. 2011; 68: 2409–2417. doi: 10.1007/s00018-011-0703-9. pmid:21667064
[38]
Archin NM, Vaidya NK, Kuruc JD, Liberty AL, Wiegand A, Kearney MF, et al. Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 infection without accelerating the decay of latent infection. Proc Natl Acad Sci USA 2012; 109: 9523–9528. doi: 10.1073/pnas.1120248109. pmid:22645358
[39]
Gay C, Dibben O, Anderson JA, Stacey A, Mayo AJ, Norris PJ, et al. Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy. PLoS One 2011; 6:e19617. doi: 10.1371/journal.pone.0019617. pmid:21573003
[40]
Soriano-Sarabia N, Sandvold H, Jomaa H, Kubin T, Bein G, Hackstein H. Primary MHC-class II+ cells are necessary to promote resting Vδ2 cells expansion in response to (E)-4-Hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate J Immunol. 2012; 189: 5212–5222. doi: 10.4049/jimmunol.1200093. pmid:23105138
[41]
Strain MC, Lada SM, Luong T, Rought SE, Gianella S, Terry VH, et al. Highly Precise Measurement of HIV DNA by Droplet Digital PCR. PLoS One 2013; 8: 1–8, e55943. doi: 10.1371/journal.pone.0055943
