Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada; Centre de recherche du centre hospitalier de l'Université de Montréal (CR-CHUM), Montréal, QC, Canada.
Service of Molecular Virology, Department of Molecular Biology (DBM), Université libre de Bruxelles (ULB), 6041 Gosselies, Belgium.
Cell Rep. 2024 Jul 23;43(7):114414. doi: 10.1016/j.celrep.2024.114414. Epub 2024 Jun 28.
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.
肠道环境通过涉及肠道归巢维生素 A 衍生的视黄酸（RA）的机制促进 HIV-1 感染，RA 可转录重编程 CD4 T 细胞以增加 HIV-1 的复制/生长。一致地，在接受抗逆转录病毒治疗（ART）的 HIV-1（PWH）人群中，肠道浸润的 CD4 T 细胞携带具有复制能力的病毒储存库。有趣的是，在接受 ART 治疗的 PWH 中，整合感染结肠巨噬细胞（由单核细胞补充的池）是一种罕见事件，因此质疑 RA 对巨噬细胞的影响。在这里，我们证明 RA 增强了 R5 但不能增强 X4 HIV-1 在单核细胞衍生的巨噬细胞（MDM）中的复制。RNA 测序、基因集变异分析和 HIV 相互作用者 NCBI 数据库查询揭示了 RA 介导的与代谢/炎症过程和 HIV-1 抵抗/依赖性因素相关的转录重编程。功能验证揭示了 RA 作用的进入后机制，包括 SAMHD1 调节的逆转录和 CDK9/RNA 聚合酶 II（RNAPII）依赖性转录，受雷帕霉素（mTOR）的控制。这些结果支持了一种模型，即未接受 ART 治疗的 PWH 肠道中的巨噬细胞以 mTOR 敏感的方式促进病毒的复制/传播。
