New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy

作者：Wacleche Vanessa Sue; Goulet Jean Philippe; Gosselin Annie; Monteiro Patricia; Soudeyns Hugo; Fromentin Remi; Jenabian Mohammad Ali; Vartanian Shant; Deeks Steven G; Chomont Nicolas; Routy Jean Pierre; Ancuta Petronela

来源：Retrovirology, 2016, 13(1): 59.

DOI：10.1186/s12977-016-0293-6

• Human
• Th17
• CCR6
• CCR4
• CXCR3
• HIV reservoirs
• ART

Background: Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown.
Results: Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6(+) CCR4(+) (Th17) and CCR6(+) CXCR3(+) (Th1Th17) subsets, we reveal the existence of two novel CCR6(+) subsets, lacking (double negative, CCR6(+) DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6(+) DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6+ DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6(+) DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6(+) DN cells were the most predominant CCR6(+) subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6(+) DN of ART-treated individuals.
Conclusions: Together, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6(+) CD4(+) T-cells and support the major contribution of CCR6(+) DN cells to HIV persistence during ART.

• 出版日期2016-8-24