Impaired Th17 polarization of phenotypically naive CD4(+) T-cells during chronic HIV-1 infection and potential restoration with early ART.
BACKGROUND
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).


RESULTS
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.


CONCLUSIONS
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.
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. sdafonseca7@gmail.com.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. sdafonseca7@gmail.com.
Sandrina
S
DaFonseca
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. julia.niessl@web.de.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. julia.niessl@web.de.
Julia
J
Niessl
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. sylvia.pouvreau@gmail.com.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. sylvia.pouvreau@gmail.com.
Sylvia
S
Pouvreau
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. vanessa.sue.wacleche@umontreal.ca.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. vanessa.sue.wacleche@umontreal.ca.
Vanessa Sue
VS
Wacleche
CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. annie.gosselin.chum@gmail.com.
Annie
A
Gosselin
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. cleret.aurelie@gmail.com.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. cleret.aurelie@gmail.com.
Aurélie
A
Cleret-Buhot
Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada. nicole.bernard@mcgill.ca.|Research Institute of the McGill University Health Centre, Montreal, QC, Canada. nicole.bernard@mcgill.ca.|Division of Experimental Medicine, McGill University, Montreal, QC, Canada. nicole.bernard@mcgill.ca.|Division of Clinical Immunology, McGill University Health Centre, Montreal, QC, Canada. nicole.bernard@mcgill.ca.
Nicole
N
Bernard
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. c.tremblay@umontreal.ca.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. c.tremblay@umontreal.ca.
Cécile
C
Tremblay
Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada. jenabian.mohammad-ali@uqam.ca.|Research Institute of the McGill University Health Centre, Montreal, QC, Canada. jenabian.mohammad-ali@uqam.ca.|Département des sciences Biologiques, Université du Québec à Montréal, Montreal, QC, Canada. jenabian.mohammad-ali@uqam.ca.
Mohammad-Ali
MA
Jenabian
Chronic Viral Illness Service, McGill University Health Centre, Montreal, QC, Canada. jean-pierre.routy@mcgill.ca.|Research Institute of the McGill University Health Centre, Montreal, QC, Canada. jean-pierre.routy@mcgill.ca.|Division of Hematology, McGill University Health Centre, Montreal, QC, Canada. jean-pierre.routy@mcgill.ca.
Jean-Pierre
JP
Routy
Faculty of Medicine, Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada. petronela.ancuta@umontreal.ca.|CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal, QC, H2X 0A9, Canada. petronela.ancuta@umontreal.ca.
Petronela
P
Ancuta
D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation; D002908:Chronic Disease; D003430:Cross-Sectional Studies; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008137:Longitudinal Studies; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
D044966:Anti-Retroviral Agents