Pharmacological Inhibition of PPAR? Reverses HIV Latency but Prevents Viral Production/Infectivity while Boosting Th17 Functions

In addition to HIV-permissiveness factors, Th17-cells express PPAR?, a transcriptional repressor of specific genes including ROR?t and HIV. Here, we investigated the effect of PPAR? pharmacological inhibition on HIV replication and Th17 functions. As predicted, T-cell receptor triggering in the presence of the PPARG antagonist T0070907 increased IL-17A production and cell-associated HIV-RNA levels in T-cells of HIV-infected ART-treated individuals. Unexpectedly, T0070907 inhibited HIV-RNA release/viral outgrowth ex vivo and transmitted/founder HIV replication in vitro. Whole genome RNA-sequencing revealed multiple genes/pathways modulated by T0070907, including those involved in HIV-permissiveness (e.g., CCR5, furin) versus HIV-restriction (e.g., TRIM22, BST2, miR29), as well as Th17-effector functions (e.g., ROR?t, STAT3, BCL6, IL-17A/F, IL-21, IL-22, IL-26). Of note, T0070907 boosted IL-21, a cytokine exhibiting immune-regulatory and miR-29-mediated antiviral properties. miR-29 antagomir failed to restore HIV replication in T0070907-treated T-cells, indicative of a pleiotropic antiviral program triggered by PPARG antagonism. Overall design: 8 patients, 2 conditions: DMSO, T007