Retinoic acid enhances HIV-1 reverse transcription and transcription in macrophages via mTOR-modulated mechanisms

The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing vitamin A-derived retinoic acid (RA), which transcriptionally reprograms CD4+ T cells for increased HIV-1 replication/outgrowth. Consistently, colon-infiltrating CD4+ T cells carry replication-competent viral reservoirs in people with HIV-1 (PWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by monocytes, represents a rare event in ART-treated PWH, thus questioning the effect of RA on macrophages. Here, we demonstrate that RA enhances R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA sequencing, gene set variation analysis, and HIV interactor NCBI database interrogation reveal RA-mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations uncover post-entry mechanisms of RA action including SAMHD1-modulated reverse transcription and CDK9/RNA polymerase II (RNAPII)-dependent transcription under the control of mammalian target of rapamycin (mTOR). These results support a model in which macrophages residing in the intestine of ART-untreated PWH contribute to viral replication/dissemination in an mTOR-sensitive manner. [Display omitted] •Retinoic acid (RA) enhances R5 but not X4 HIV-1 replication in macrophages•RA facilitates HIV-1 replication via post-entry mechanisms•RA blunts SAMHD1-mediated HIV-1 restriction via mTOR-modulated mechanisms•RA increases the CDK9/RNAPII-dependent HIV-1 transcription Dias et al. investigated the effects of retinoic acid (RA), a gut-homing elixir, on macrophages. RA boosts permissiveness to HIV-1 replication by facilitating multiple steps of the viral replication cycle. By analyzing the effect of RA on gene expression, the authors identify new mechanisms of RA action, namely SAMHD1/CDK9/RNAPII-dependent and mTOR-modulated mechanisms.