Nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block in latency
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.
Authors
- Jakub Wadas (ORCID: https://orcid.org/0000-0003-1675-6286)
- Maryam Bendoumou
- Véronique Avettand-Fènoël (ORCID: https://orcid.org/0000-0002-7022-2990)
- Alexandra Dorman (ORCID: https://orcid.org/0000-0002-4997-1743)
- Alexander Pasternak (ORCID: https://orcid.org/0000-0002-4097-4251)
- Coca Necsoi
- Gilbert Mchantaf (ORCID: https://orcid.org/0000-0002-2094-0492)
- Monika Bociąga‐Jasik (ORCID: https://orcid.org/0000-0002-6474-0177)
- Alessandro Marcello (ORCID: https://orcid.org/0000-0002-8903-8202)
- Haider Ali
- Carine Van Lint (ORCID: https://orcid.org/0000-0002-2219-2862)
- Krzysztof Pyrć (ORCID: https://orcid.org/0000-0002-3867-7688)
- Lorena Nestola
- Antoine Dutilleul
- Paolo Maiuri (ORCID: https://orcid.org/0000-0001-5079-445X)
- Anna Kula (ORCID: https://orcid.org/0000-0001-8404-2176)
- Stéphane De Wit
- Aurelija Valaitienė
Institutions
- Université d'Orléans (FR)
- Jagiellonian University (PL)
- Centre National de la Recherche Scientifique (FR)
- Université Libre de Bruxelles (BE)
- Inserm (FR)
- Université Paris Cité (FR)
- Amsterdam Neuroscience (NL)
- Institut Cochin (FR)
- Centre hospitalier universitaire d'Orléans (FR)
- Amsterdam University Medical Centers (NL)
- University of Naples Federico II (IT)
- University of Amsterdam (NL)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1038/s41467-025-57290-y
- Citations
- 5
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 5.18
Funders
- Gilead Sciences
- ViiV Healthcare
- Les Amis des Instituts Pasteur à Bruxelles
- Institut National de la Santé et de la Recherche Médicale
- ZonMw
- Fonds De La Recherche Scientifique - FNRS
- Narodowe Centrum Nauki
- Narodowym Centrum Nauki
- Associazione Italiana per la Ricerca sul Cancro
- Koning Boudewijnstichting
- Uniwersytet Jagielloński w Krakowie
- Ministero dell'Università e della Ricerca
- National Institutes of Health
- Medical Research Council
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases