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

Agnieszka Dorman, Maryam Bendoumou, Aurelija Valaitienė, Jakub Wadas, Haider Ali, Antoine Dutilleul, Paolo Maiuri, Lorena Nestola, Monika Bociaga-Jasik, Gilbert Mchantaf, Coca Necsoi, Stéphane Wit, Véronique Avettand-Fenoël, Alessandro Marcello, Krzysztof Pyrc (), Alexander O. Pasternak (), Carine Lint () and Anna Kula-Pacurar ()
Additional contact information
Agnieszka Dorman: Jagiellonian University
Maryam Bendoumou: Université Libre de Bruxelles (ULB)
Aurelija Valaitienė: University of Amsterdam
Jakub Wadas: Jagiellonian University
Haider Ali: Jagiellonian University
Antoine Dutilleul: Université Libre de Bruxelles (ULB)
Paolo Maiuri: Università degli Studi di Napoli “Federico II”
Lorena Nestola: Université Libre de Bruxelles (ULB)
Monika Bociaga-Jasik: Jagiellonian University Medical College
Gilbert Mchantaf: Institut Cochin
Coca Necsoi: Université Libre de Bruxelles (ULB)
Stéphane Wit: Université Libre de Bruxelles (ULB)
Véronique Avettand-Fenoël: Institut Cochin
Alessandro Marcello: The International Centre for Genetic Engineering and Biotechnology (ICGEB)
Krzysztof Pyrc: Jagiellonian University
Alexander O. Pasternak: University of Amsterdam
Carine Lint: Université Libre de Bruxelles (ULB)
Anna Kula-Pacurar: Jagiellonian University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57290-y

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