TY - JOUR
T1 - Pharmacological inhibition of ppary boosts hiv reactivation and th17 effector functions, while preventing progeny virion release and de novo infection
AU - Planas, Delphine
AU - Fert, Augustine
AU - Zhang, Yuwei
AU - Goulet, Jean Philippe
AU - Richard, Jonathan
AU - Finzi, Andrés
AU - Ruiz, Maria Julia
AU - Marchand, Laurence Raymond
AU - Chatterjee, Debashree
AU - Chen, Huicheng
AU - Salinas, Tomas Raul Wiche
AU - Gosselin, Annie
AU - Cohen, Eric A.
AU - Routy, Jean Pierre
AU - Chomont, Nicolas
AU - Ancuta, Petronela
N1 - Publisher Copyright:
© 2020 Pathogens and Immunity.
PY - 2020/9/30
Y1 - 2020/9/30
N2 - The frequency and functions of Th17-polarized CCR6+RORyt+CD4+ T cells are rapidly compro-mised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of peroxisome pro-liferator-activated receptor gamma (PPARy), which acts as a transcriptional repressor of the HIV provirus and the rorc gene, which encodes for the Th17-specific master regulator RORyt. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism lim-ited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication in vitro. Mechanistically, PPARy inhibition in CCR6+CD4+ T cells induced the upreg-ulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for consider-ing PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediat-ed mucosal immunity in ART-treated PLWH.
AB - The frequency and functions of Th17-polarized CCR6+RORyt+CD4+ T cells are rapidly compro-mised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of peroxisome pro-liferator-activated receptor gamma (PPARy), which acts as a transcriptional repressor of the HIV provirus and the rorc gene, which encodes for the Th17-specific master regulator RORyt. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism lim-ited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication in vitro. Mechanistically, PPARy inhibition in CCR6+CD4+ T cells induced the upreg-ulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for consider-ing PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediat-ed mucosal immunity in ART-treated PLWH.
KW - ART
KW - CD4+ T cells
KW - HIV-1
KW - IL-21
KW - PPARy
KW - Th17
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UR - http://www.scopus.com/inward/citedby.url?scp=85092937949&partnerID=8YFLogxK
U2 - 10.20411/pai.v5i1.348
DO - 10.20411/pai.v5i1.348
M3 - Article
C2 - 33089034
AN - SCOPUS:85092937949
SN - 2469-2964
VL - 5
SP - 177
EP - 239
JO - Pathogens and Immunity
JF - Pathogens and Immunity
IS - 1
ER -