Nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block in latency

• Published in: Nature communications Vol. 16; no. 1; pp. 2078 - 15
• Main Authors: Dorman, Agnieszka, Bendoumou, Maryam, Valaitienė, Aurelija, Wadas, Jakub, Ali, Haider, Dutilleul, Antoine, Maiuri, Paolo, Nestola, Lorena, Bociaga-Jasik, Monika, Mchantaf, Gilbert, Necsoi, Coca, De Wit, Stéphane, Avettand-Fenoël, Véronique, Marcello, Alessandro, Pyrc, Krzysztof, Pasternak, Alexander O., Van Lint, Carine, Kula-Pacurar, Anna
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.02.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/35; 14/63; 38/1; 38/109; 38/32; 38/77; 38/88; 38/89; 38/90; 631/326/596/2557; 631/337/1645/2052; Active Transport, Cell Nucleus; Antiretroviral therapy; Biotechnology; Cell Nucleus - metabolism; Cell Nucleus - virology; DNA methylation; Epigenetics; Exosome Multienzyme Ribonuclease Complex - metabolism; Gene regulation; HEK293 Cells; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - genetics; HIV-1 - physiology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Latency; multidisciplinary; Post-transcription; Proteins; Retention; rev Gene Products, Human Immunodeficiency Virus - genetics; rev Gene Products, Human Immunodeficiency Virus - metabolism; Ribonucleic acid; RNA; RNA Helicases; RNA Processing, Post-Transcriptional; RNA Splicing; RNA transport; RNA, Viral - genetics; RNA, Viral - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Science (multidisciplinary); Viral infections; Virology; Virus Activation; Virus Latency - genetics; Virus Replication
• DOI: 10.1038/s41467-025-57290-y
• ISSN: 2041-1723

HIV-1 latency is mainly characterized at transcriptional level, and little is known about post-transcriptional mechanisms and their contribution to reactivation. The viral protein Rev controls the nucleocytoplasmic export of unspliced and singly-spliced RNA that is central to proviral replication-competence and is therefore a prerequisite for efficient viral reactivation during the “shock-and-kill” cure therapy. Here we show that during infection and reactivation, unspliced HIV-1 RNA is a subject to complex and dynamic regulation by the Rev cofactor MATR3 and the MTR4 cofactor of the nuclear exosome. MATR3 and MTR4 coexist in the same ribonucleoprotein complex functioning to either maintain or degrade the RNA, respectively, with Rev orchestrating this regulatory switch. Moreover, we provide evidence of nuclear retention of unspliced HIV-1 RNA in ex vivo cultures from 22 ART-treated people with HIV, highlighting a reversible post-transcriptional block to viral RNA nucleocytoplasmic export that is relevant to the design of curative interventions. In their study, Dorman and Bendoumou et al., reveal a post-transcriptional regulation of unspliced HIV-1 RNA by host factors MATR3, MTR4, and the viral protein Rev, identifying a previously uncharacterized post-transcriptional block in nucleocytoplasmic export, which plays a crucial role in HIV-1 latency and reactivation.