title: New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.|Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
authors.forename: Vanessa Sue
authors.initials: VS
authors.lastname: Wacleche
authors.affiliation: Caprion, Montreal, QC, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Goulet
authors.affiliation: Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
authors.forename: Annie
authors.initials: A
authors.lastname: Gosselin
authors.affiliation: Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.|Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
authors.forename: Patricia
authors.initials: P
authors.lastname: Monteiro
authors.affiliation: Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.|Unité d'immunopathologie virale, Centre de recherche du CHU Sainte-Justine, Montreal, QC, Canada.
authors.forename: Hugo
authors.initials: H
authors.lastname: Soudeyns
authors.affiliation: Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
authors.forename: Rémi
authors.initials: R
authors.lastname: Fromentin
authors.affiliation: Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, QC, Canada.
authors.forename: Mohammad-Ali
authors.initials: MA
authors.lastname: Jenabian
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Shant
authors.initials: S
authors.lastname: Vartanian
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.|Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chomont
authors.affiliation: Chronic Viral Illness Service and Research Institute, McGill University Health Centre, Montreal, QC, Canada.|Division of Hematology, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Routy
authors.affiliation: Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada. petronela.ancuta@umontreal.ca.|Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada. petronela.ancuta@umontreal.ca.
authors.forename: Petronela
authors.initials: P
authors.lastname: Ancuta
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D003430:Cross-Sectional Studies; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory; D008137:Longitudinal Studies; D054398:Receptors, CCR4 / Q000032:analysis; D054399:Receptors, CCR6 / Q000032:analysis; D054367:Receptors, CXCR3 / Q000032:analysis; D058504:Th17 Cells / Q000187:drug effects* / Q000502:physiology* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C515354:CCR4 protein, human; C106311:CCR6 protein, human; C515187:CXCR3 protein, human; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D054367:Receptors, CXCR3
keywords: ART; CCR4; CCR6; CXCR3; HIV reservoirs; Human; Th17