DaFonseca Sandrina, Niessl Julia, Pouvreau Sylvia, Wacleche Vanessa Sue, Gosselin Annie, Cleret-Buhot Aurélie, Bernard Nicole, Tremblay Cécile, Jenabian Mohammad-Ali, Routy Jean-Pierre, Ancuta Petronela
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada.
CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada.
Retrovirology. 2015 Apr 30;12:38. doi: 10.1186/s12977-015-0164-6.
Depletion of mucosal Th17 cells during HIV/SIV infections is a major cause for microbial translocation, chronic immune activation, and disease progression. Mechanisms contributing to Th17 deficit are not fully elucidated. Here we investigated alterations in the Th17 polarization potential of naive-like CD4(+) T-cells, depletion of Th17-commited subsets during HIV pathogenesis, and Th17 restoration in response to antiretroviral therapy (ART).
Peripheral blood CD4(+) T-cells expressing a naive-like phenotype (CD45RA(+)CCR7(+)) from chronically HIV-infected subjects receiving ART (CI on ART; median CD4 counts 592 cells/μl; viral load: <50 HIV-RNA copies/ml; time since infection: 156 months) compared to uninfected controls (HIV-) were impaired in their survival and Th17 polarization potential in vitro. In HIV- controls, IL-17A-producing cells mainly originated from naive-like T-cells with a regulatory phenotype (nTregs: CD25(high)CD127(-)FoxP3(+)) and from CD25(+)CD127(+)FoxP3(-) cells (DP, double positive). Th17-polarized conventional naive CD4(+) T-cells (nT: CD25(-)CD127(+)FoxP3(-)) also produced IL17A, but at lower frequency compared to nTregs and DP. In CI on ART subjects, the frequency/counts of nTreg and DP were significantly diminished compared to HIV- controls, and this paucity was further associated with decreased proportions of memory T-cells producing IL-17A and expressing Th17 markers (CCR6(+)CD26(+)CD161(+), mTh17). nTregs and DP compared to nT cells harbored superior levels of integrated/non-integrated HIV-DNA in CI on ART subjects, suggesting that permissiveness to integrative/abortive infection contributes to impaired survival and Th17 polarization of lineage-committed cells. A cross-sectional study in CI on ART subjects revealed that nTregs, DP and mTh17 counts were negatively correlated with the time post-infection ART was initiated and positively correlated with nadir CD4 counts. Finally, a longitudinal analysis in a HIV primary infection cohort demonstrated a tendency for increased nTreg, DP, and mTh17 counts with ART initiation during the first year of infection.
These results support a model in which the paucity of phenotypically naive nTregs and DP cells, caused by integrative/abortive HIV infection and/or other mechanisms, contributes to Th17 deficiency in HIV-infected subjects. Early ART initiation, treatment intensification with integrase inhibitors, and/or other alternative interventions aimed at preserving/restoring the pool of cells prone to acquire Th17 functions may significantly improve mucosal immunity in HIV-infected subjects.
HIV/SIV感染期间黏膜Th17细胞耗竭是微生物易位、慢性免疫激活和疾病进展的主要原因。导致Th17细胞缺乏的机制尚未完全阐明。在此，我们研究了初始样CD4(+)T细胞的Th17极化潜能的改变、HIV发病过程中Th17定向亚群的耗竭以及抗逆转录病毒治疗（ART）后Th17的恢复情况。
与未感染的对照组（HIV-）相比，接受ART的慢性HIV感染受试者（ART治疗的慢性感染者；CD4计数中位数为592个细胞/μl；病毒载量：<50个HIV-RNA拷贝/ml；感染时间：156个月）外周血中表达初始样表型（CD45RA(+)CCR7(+)）的CD4(+)T细胞在体外的存活和Th17极化潜能受损。在HIV-对照组中，产生IL-17A的细胞主要来源于具有调节表型的初始样T细胞（nTregs：CD25(高)CD127(-)FoxP3(+)）和CD25(+)CD127(+)FoxP3(-)细胞（DP，双阳性）。Th17极化的传统初始CD4(+)T细胞（nT：CD25(-)CD127(+)FoxP3(-)）也产生IL17A，但与nTregs和DP相比频率较低。在接受ART治疗的慢性感染者中，与HIV-对照组相比，nTreg和DP的频率/数量显著减少，这种缺乏还与产生IL-17A并表达Th17标志物（CCR6(+)CD26(+)CD161(+)，mTh17）的记忆T细胞比例降低有关。与nT细胞相比，接受ART治疗的慢性感染者中的nTregs和DP含有更高水平的整合/未整合HIV-DNA，这表明对整合性/顿挫性感染的易感性导致了定向细胞的存活受损和Th17极化。对接受ART治疗的慢性感染者的横断面研究表明，nTregs、DP和mTh17计数与开始ART治疗后的感染时间呈负相关，与最低点CD4计数呈正相关。最后，对HIV原发性感染队列的纵向分析表明，在感染的第一年开始ART治疗后，nTreg、DP和mTh17计数有增加的趋势。
这些结果支持一种模型，即由整合性/顿挫性HIV感染和/或其他机制导致的表型初始nTregs和DP细胞缺乏，促成了HIV感染受试者的Th17细胞缺乏。早期开始ART治疗、使用整合酶抑制剂加强治疗和/或其他旨在保存/恢复易于获得Th17功能的细胞池的替代干预措施，可能会显著改善HIV感染受试者的黏膜免疫。
