Retinoic Acid Boosts HIV-1 Replication in Macrophages <i>via</i> CCR5/SAMHD1-Dependent and mTOR-Modulated Mechanisms

ABSTRACT The intestinal environment facilitates HIV-1 infection via mechanisms involving the gut-homing elixir retinoic acid (RA), which transcriptionally reprograms CD4 + T-cells for increased HIV-1 permissiveness. Consistently, colon-infiltrating CD4 + T-cells carry replication-competent viral reservoirs in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Intriguingly, integrative infection in colon macrophages, a pool replenished by circulating monocytes, represents a rare event in ART-treated PLWH, thus questioning on HIV-1 permissiveness in gut-resident macrophages. Here, we demonstrate that RA significantly boosts R5 but not X4 HIV-1 replication in monocyte-derived macrophages (MDMs). RNA-Sequencing, Gene Set Variation Analysis, and HIV interactor NCBI database interrogation, revealed RA- mediated transcriptional reprogramming associated with metabolic/inflammatory processes and HIV-1 resistance/dependency factors. Functional validations pointed to mechanisms of RA action, including CCR5 upregulation and SAMHD1 phosphorylation under the control of mTOR. These results support a model in which intestinal MDM contribute to viral replication/dissemination before ART and upon treatment interruption in mTOR-sensitive manner. Figure 1: