biostudies-literatureDias JNIAID NIH HHS114414https://www.ebi.ac.uk/biostudies/studies/S-EPMC11341200biostudies-literatureUnknown43(7)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.Cell reportsRetinoic acid enhances HIV-1 reverse transcription and transcription in macrophages via mTOR-modulated mechanisms.PMC11341200UM1 AI164562Raymond Marchand LLodge RCaballero RECohen EAAncuta PVan Lint CNgassaki Yoka CDGabriel EMWiche Salinas TRCattin ADutilleul ABendoumou MFert ARouty JPGoulet JPDias JfalseRetinoic 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.2024-01-01T00:00:00Z2024 Jul2024-11-20T06:12:22.919Z2024-11-20T06:12:22.919ZS-EPMC113412003894364310.1016/j.celrep.2024.114414