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

Retrovirology

Petronela Ancuta¹  Jean-Pierre Routy³  Mohammad-Ali Jenabian⁴  Cécile Tremblay¹  Nicole Bernard²  Aurélie Cleret-Buhot¹  Annie Gosselin¹  Vanessa Sue Wacleche¹  Sylvia Pouvreau¹  Julia Niessl¹  Sandrina DaFonseca¹ 

[1]CHUM-Research Centre, 900 rue Saint-Denis, Tour Viger R, room R09.416, Montreal H2X 0A9, QC, Canada

[2]Division of Clinical Immunology, McGill University Health Centre, Montreal, QC, Canada

[3]Division of Hematology, McGill University Health Centre, Montreal, QC, Canada

[4]Département des sciences Biologiques, Université du Québec à Montréal, Montreal, QC, Canada

关键词: Antiretroviral therapy;    CD127;    CD25;    Regulatory T cells;    Th17 cells;    HIV;   

Others  :  1210152
DOI  :  10.1186/s12977-015-0164-6

 received in 2014-11-10, accepted in 2015-04-02,  发布年份 2015

【 摘 要 】

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^highCD127⁻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.

【 授权许可】

   
2015 DaFonseca et al.; licensee BioMed Central.

【 图 表 】

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