1. Retinoic acid enhances HIV-1 reverse transcription and transcription in macrophages via mTOR-modulated mechanisms.
- Author
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Dias J, Cattin A, Bendoumou M, Dutilleul A, Lodge R, Goulet JP, Fert A, Raymond Marchand L, Wiche Salinas TR, Ngassaki Yoka CD, Gabriel EM, Caballero RE, Routy JP, Cohen ÉA, Van Lint C, and Ancuta P
- Subjects
- Humans, Reverse Transcription drug effects, SAM Domain and HD Domain-Containing Protein 1 metabolism, SAM Domain and HD Domain-Containing Protein 1 genetics, HIV Infections virology, HIV Infections drug therapy, HIV Infections metabolism, Cyclin-Dependent Kinase 9 metabolism, RNA Polymerase II metabolism, Transcription, Genetic drug effects, Macrophages metabolism, Macrophages virology, Macrophages drug effects, HIV-1 drug effects, TOR Serine-Threonine Kinases metabolism, Tretinoin pharmacology, Virus Replication drug effects
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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