In HIV/SIV-infected humans and rhesus macaques (RMs), a severe depletion of intestinal CD4+ T-cells producing interleukin IL-17 and IL-22 associates with loss of mucosal integrity and chronic immune activation. However, little is known about the function of IL-17 and IL-22 producing cells during lentiviral infections. Here, we longitudinally determined the levels and functions of IL-17, IL-22 and IL-17/IL-22 producing CD4+ T-cells in blood, lymph node and colorectum of SIV-infected RMs, as well as how they recover during effective ART and are affected by ART interruption. Intestinal IL-17 and IL-22 producing CD4+ T-cells are polyfunctional in SIV-uninfected RMs, with the large majority of cells producing four or five cytokines. SIV infection induced a severe dysfunction of colorectal IL-17, IL-22 and IL-17/IL-22 producing CD4+ T-cells, the extent of which associated with the levels of immune activation (HLA-DR+CD38+), proliferation (Ki-67+) and CD4+ T-cell counts before and during ART. Additionally, Th17 cell function during ART negatively correlated with residual plasma viremia and levels of sCD163, a soluble marker of inflammation and disease progression. Furthermore, IL-17 and IL-22 producing cell frequency and function at various pre, on, and off-ART experimental points associated with and predicted total SIV-DNA content in the colorectum and blood. While ART restored Th22 cell function to levels similar to pre-infection, it did not fully restore Th17 cell function, and all cell types were rapidly and severely affected—both quantitatively and qualitatively—after ART interruption. In conclusion, intestinal IL-17 producing cell function is severely impaired by SIV infection, not fully normalized despite effective ART, and strongly associates with inflammation as well as SIV persistence off and on ART. As such, strategies able to preserve and/or regenerate the functions of these CD4+ T-cells central for mucosal immunity are critically needed in future HIV cure research.
References
[1]
Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, et al. (1998) Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280: 427–431. pmid:9545219 doi: 10.1126/science.280.5362.427
[2]
Estes JD, Harris LD, Klatt NR, Tabb B, Pittaluga S, et al. (2010) Damaged intestinal epithelial integrity linked to microbial translocation in pathogenic simian immunodeficiency virus infections. PLoS pathogens 6: e1001052. doi: 10.1371/journal.ppat.1001052. pmid:20808901
[3]
Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, et al. (2004) Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. The Journal of experimental medicine 200: 761–770. pmid:15365095 doi: 10.1084/jem.20041196
[4]
Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, et al. (2004) CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. The Journal of experimental medicine 200: 749–759. pmid:15365096 doi: 10.1084/jem.20040874
[5]
Schmitt N, Ueno H (2015) Regulation of human helper T cell subset differentiation by cytokines. Current opinion in immunology 34: 130–136. doi: 10.1016/j.coi.2015.03.007. pmid:25879814
[6]
Wilson CB, Rowell E, Sekimata M (2009) Epigenetic control of T-helper-cell differentiation. Nature reviews Immunology 9: 91–105. doi: 10.1038/nri2487. pmid:19151746
[7]
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annual review of immunology 27: 485–517. doi: 10.1146/annurev.immunol.021908.132710. pmid:19132915
[8]
Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Current opinion in immunology 19: 652–657. pmid:17766098 doi: 10.1016/j.coi.2007.07.020
[9]
Korn T, Oukka M, Kuchroo V, Bettelli E (2007) Th17 cells: effector T cells with inflammatory properties. Seminars in immunology 19: 362–371. pmid:18035554 doi: 10.1016/j.smim.2007.10.007
[10]
Chen Z, O'Shea JJ (2008) Th17 cells: a new fate for differentiating helper T cells. Immunol Res 41: 87–102. doi: 10.1007/s12026-007-8014-9. pmid:18172584
[11]
Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, et al. (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature immunology 8: 639–646. pmid:17486092 doi: 10.1038/ni1467
[12]
Lee JS, Cua DJ (2015) IL-26 AMPs up the TH17 arsenal. Nature immunology 16: 897–898. doi: 10.1038/ni.3256. pmid:26287587
[13]
Meller S, Di Domizio J, Voo KS, Friedrich HC, Chamilos G, et al. (2015) TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26. Nature immunology 16: 970–979. doi: 10.1038/ni.3211. pmid:26168081
[14]
Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature immunology 10: 857–863. doi: 10.1038/ni.1767. pmid:19578369
[15]
Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nature immunology 10: 864–871. doi: 10.1038/ni.1770. pmid:19578368
[16]
Ramirez JM, Brembilla NC, Sorg O, Chicheportiche R, Matthes T, et al. (2010) Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. European journal of immunology 40: 2450–2459. doi: 10.1002/eji.201040461. pmid:20706985
[17]
Leung JM, Davenport M, Wolff MJ, Wiens KE, Abidi WM, et al. (2014) IL-22-producing CD4+ cells are depleted in actively inflamed colitis tissue. Mucosal immunology 7: 124–133. doi: 10.1038/mi.2013.31. pmid:23695510
[18]
Pickert G, Neufert C, Leppkes M, Zheng Y, Wittkopf N, et al. (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. The Journal of experimental medicine 206: 1465–1472. doi: 10.1084/jem.20082683. pmid:19564350
[19]
Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, et al. (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. The Journal of clinical investigation 118: 534–544. doi: 10.1172/JCI33194. pmid:18172556
[20]
Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, et al. (2004) IL-22 increases the innate immunity of tissues. Immunity 21: 241–254. pmid:15308104 doi: 10.1016/j.immuni.2004.07.007
[21]
Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, et al. (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14: 282–289. doi: 10.1038/nm1720. pmid:18264109
[22]
O'Connor W Jr., Zenewicz LA, Flavell RA (2010) The dual nature of T(H)17 cells: shifting the focus to function. Nature immunology 11: 471–476. doi: 10.1038/ni.1882. pmid:20485275
[23]
Ota N, Wong K, Valdez PA, Zheng Y, Crellin NK, et al. (2011) IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nature immunology 12: 941–948. doi: 10.1038/ni.2089. pmid:21874025
[24]
Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, et al. (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14: 275–281. doi: 10.1038/nm1710. pmid:18264110
[25]
Kelly MN, Kolls JK, Happel K, Schwartzman JD, Schwarzenberger P, et al. (2005) Interleukin-17/interleukin-17 receptor-mediated signaling is important for generation of an optimal polymorphonuclear response against Toxoplasma gondii infection. Infection and immunity 73: 617–621. pmid:15618203 doi: 10.1128/iai.73.1.617-621.2005
[26]
Huang W, Na L, Fidel PL, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. The Journal of infectious diseases 190: 624–631. pmid:15243941 doi: 10.1086/422329
[27]
Higgins SC, Jarnicki AG, Lavelle EC, Mills KH (2006) TLR4 mediates vaccine-induced protective cellular immunity to Bordetella pertussis: role of IL-17-producing T cells. Journal of immunology 177: 7980–7989. doi: 10.4049/jimmunol.177.11.7980
[28]
Rudner XL, Happel KI, Young EA, Shellito JE (2007) Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection. Infection and immunity 75: 3055–3061. pmid:17403873 doi: 10.1128/iai.01329-06
[29]
Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, et al. (2008) Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112: 2826–2835. doi: 10.1182/blood-2008-05-159301. pmid:18664624
[30]
Micci L, Cervasi B, Ende ZS, Iriele RI, Reyes-Aviles E, et al. (2012) Paucity of IL-21-producing CD4(+) T cells is associated with Th17 cell depletion in SIV infection of rhesus macaques. Blood 120: 3925–3935. doi: 10.1182/blood-2012-04-420240. pmid:22990011
[31]
Pallikkuth S, Micci L, Ende ZS, Iriele RI, Cervasi B, et al. (2013) Maintenance of intestinal Th17 cells and reduced microbial translocation in SIV-infected rhesus macaques treated with interleukin (IL)-21. PLoS pathogens 9: e1003471. doi: 10.1371/journal.ppat.1003471. pmid:23853592
[32]
Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, et al. (2008) Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal immunology 1: 279–288. doi: 10.1038/mi.2008.14. pmid:19079189
[33]
Raffatellu M, Santos RL, Verhoeven DE, George MD, Wilson RP, et al. (2008) Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14: 421–428. doi: 10.1038/nm1743. pmid:18376406
[34]
Klatt NR, Estes JD, Sun X, Ortiz AM, Barber JS, et al. (2012) Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection. Mucosal immunology 5: 646–657. doi: 10.1038/mi.2012.38. pmid:22643849
[35]
L. Micci, E. Ryan, C. McGary, S. Paganini, G. Silvestri, et al. (2015) IL-21 Reduces Inflammation and Virus Persistence in ART-Treated SIV-Infected Macaques. Conference on Retroviruses and Opportunistic Infections (CROI). Seattle, Washington.
[36]
Klatt NR, Chomont N, Douek DC, Deeks SG (2013) Immune activation and HIV persistence: implications for curative approaches to HIV infection. Immunological reviews 254: 326–342. doi: 10.1111/imr.12065. pmid:23772629
[37]
Macal M, Sankaran S, Chun TW, Reay E, Flamm J, et al. (2008) Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses. Mucosal immunology 1: 475–488. doi: 10.1038/mi.2008.35. pmid:19079215
[38]
Brenchley JM, Paiardini M (2011) Immunodeficiency lentiviral infections in natural and non-natural hosts. Blood 118: 847–854. doi: 10.1182/blood-2010-12-325936. pmid:21505193
[39]
Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, et al. (2009) Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS pathogens 5: e1000295. doi: 10.1371/journal.ppat.1000295. pmid:19214220
[40]
Salgado M, Rallon NI, Rodes B, Lopez M, Soriano V, et al. (2011) Long-term non-progressors display a greater number of Th17 cells than HIV-infected typical progressors. Clinical immunology 139: 110–114. doi: 10.1016/j.clim.2011.02.008. pmid:21367666
[41]
Brandt L, Benfield T, Mens H, Clausen LN, Katzenstein TL, et al. (2011) Low level of regulatory T cells and maintenance of balance between regulatory T cells and TH17 cells in HIV-1-infected elite controllers. Journal of acquired immune deficiency syndromes 57: 101–108. doi: 10.1097/QAI.0b013e318215a991. pmid:21407087
[42]
Ciccone EJ, Greenwald JH, Lee PI, Biancotto A, Read SW, et al. (2011) CD4+ T cells, including Th17 and cycling subsets, are intact in the gut mucosa of HIV-1-infected long-term nonprogressors. Journal of virology 85: 5880–5888. doi: 10.1128/JVI.02643-10. pmid:21471231
[43]
Hartigan-O'Connor DJ, Abel K, Van Rompay KK, Kanwar B, McCune JM (2012) SIV replication in the infected rhesus macaque is limited by the size of the preexisting TH17 cell compartment. Science translational medicine 4: 136ra169. doi: 10.1126/scitranslmed.3003941
[44]
Kim CJ, McKinnon LR, Kovacs C, Kandel G, Huibner S, et al. (2013) Mucosal Th17 cell function is altered during HIV infection and is an independent predictor of systemic immune activation. Journal of immunology 191: 2164–2173. doi: 10.4049/jimmunol.1300829
[45]
Schuetz A, Deleage C, Sereti I, Rerknimitr R, Phanuphak N, et al. (2014) Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS pathogens 10: e1004543. doi: 10.1371/journal.ppat.1004543. pmid:25503054
[46]
Kok A, Hocqueloux L, Hocini H, Carriere M, Lefrou L, et al. (2015) Early initiation of combined antiretroviral therapy preserves immune function in the gut of HIV-infected patients. Mucosal immunology 8: 127–140. doi: 10.1038/mi.2014.50. pmid:24985081
[47]
Boniface K, Blumenschein WM, Brovont-Porth K, McGeachy MJ, Basham B, et al. (2010) Human Th17 cells comprise heterogeneous subsets including IFN-gamma-producing cells with distinct properties from the Th1 lineage. Journal of immunology 185: 679–687. doi: 10.4049/jimmunol.1000366
[48]
Shi G, Cox CA, Vistica BP, Tan C, Wawrousek EF, et al. (2008) Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. Journal of immunology 181: 7205–7213. doi: 10.4049/jimmunol.181.10.7205
[49]
Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, et al. (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proceedings of the National Academy of Sciences of the United States of America 107: 14751–14756. doi: 10.1073/pnas.1003852107. pmid:20679229
[50]
Sandler NG, Wand H, Roque A, Law M, Nason MC, et al. (2011) Plasma levels of soluble CD14 independently predict mortality in HIV infection. The Journal of infectious diseases 203: 780–790. doi: 10.1093/infdis/jiq118. pmid:21252259
[51]
Burdo TH, Lentz MR, Autissier P, Krishnan A, Halpern E, et al. (2011) Soluble CD163 made by monocyte/macrophages is a novel marker of HIV activity in early and chronic infection prior to and after anti-retroviral therapy. The Journal of infectious diseases 204: 154–163. doi: 10.1093/infdis/jir214. pmid:21628670
[52]
Leeansyah E, Malone DF, Anthony DD, Sandberg JK (2013) Soluble biomarkers of HIV transmission, disease progression and comorbidities. Current opinion in HIV and AIDS 8: 117–124. doi: 10.1097/COH.0b013e32835c7134. pmid:23274365
[53]
Paiardini M (2010) Th17 cells in natural SIV hosts. Current opinion in HIV and AIDS 5: 166–172. doi: 10.1097/COH.0b013e328335c161. pmid:20543595
[54]
Deeks SG, Tracy R, Douek DC (2013) Systemic effects of inflammation on health during chronic HIV infection. Immunity 39: 633–645. doi: 10.1016/j.immuni.2013.10.001. pmid:24138880
[55]
Paiardini M, Cervasi B, Reyes-Aviles E, Micci L, Ortiz AM, et al. (2011) Low levels of SIV infection in sooty mangabey central memory CD4(+) T cells are associated with limited CCR5 expression. Nat Med 17: 830–U197. doi: 10.1038/nm.2395. pmid:21706028
[56]
Micci L, Alvarez X, Iriele RI, Ortiz AM, Ryan ES, et al. (2014) CD4 Depletion in SIV-Infected Macaques Results in Macrophage and Microglia Infection with Rapid Turnover of Infected Cells. PLoS pathogens 10: e1004467. doi: 10.1371/journal.ppat.1004467. pmid:25356757
[57]
Amara RR, Villinger F, Altman JD, Lydy SL, O'Neil SP, et al. (2001) Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292: 69–74. pmid:11393868 doi: 10.1126/science.1058915
[58]
Vandergeeten C, Fromentin R, Merlini E, Lawani MB, DaFonseca S, et al. (2014) Cross-clade ultrasensitive PCR-based assays to measure HIV persistence in large-cohort studies. Journal of virology 88: 12385–12396. doi: 10.1128/JVI.00609-14. pmid:25122785
[59]
Nishimura Y, Sadjadpour R, Mattapallil JJ, Igarashi T, Lee W, et al. (2009) High frequencies of resting CD4+ T cells containing integrated viral DNA are found in rhesus macaques during acute lentivirus infections. Proceedings of the National Academy of Sciences of the United States of America 106: 8015–8020. doi: 10.1073/pnas.0903022106. pmid:19416840
[60]
Hansen SG, Piatak M Jr., Ventura AB, Hughes CM, Gilbride RM, et al. (2013) Immune clearance of highly pathogenic SIV infection. Nature 502: 100–104. doi: 10.1038/nature12519. pmid:24025770
