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

New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy.
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Wacleche VS, Goulet JP, Gosselin A, Monteiro P, Soudeyns H, Fromentin R, Jenabian MA, Vartanian S, Deeks SG, Chomont N, Routy JP, Ancuta P,


Wacleche VS, Goulet JP, Gosselin A, Monteiro P, Soudeyns H, Fromentin R, Jenabian MA, Vartanian S, Deeks SG, Chomont N, Routy JP, Ancuta P, (click to view)

Wacleche VS, Goulet JP, Gosselin A, Monteiro P, Soudeyns H, Fromentin R, Jenabian MA, Vartanian S, Deeks SG, Chomont N, Routy JP, Ancuta P,

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Retrovirology 2016 08 2413(1) 59 doi 10.1186/s12977-016-0293-6

Abstract
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.

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