2. Academic Validation
  3. Nuclear retention of unspliced HIV-1 RNA as a reversible post-transcriptional block in latency

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

  • Nat Commun. 2025 Feb 28;16(1):2078. doi: 10.1038/s41467-025-57290-y.
Agnieszka Dorman # 1 2,  Maryam Bendoumou # 3,  Aurelija Valaitienė 4,  Jakub Wadas 1 2,  Haider Ali 1 2,  Antoine Dutilleul 3,  Paolo Maiuri 5,  Lorena Nestola 3,  Monika Bociaga-Jasik 6,  Gilbert Mchantaf 7 8 9,  Coca Necsoi 10,  Stéphane De Wit 10,  Véronique Avettand-Fenoël 7 8 9,  Alessandro Marcello 11,  Krzysztof Pyrc 12,  Alexander O Pasternak 13,  Carine Van Lint 14,  Anna Kula-Pacurar 15
Affiliations

Affiliations

  • 1 Laboratory of Molecular Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.
  • 2 Doctoral School of Exact and Natural Sciences, Jagiellonian University, Lojasiewicza 11, 30-348, Krakow, Poland.
  • 3 Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium.
  • 4 Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
  • 5 Dept of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli "Federico II", Naples, Italy.
  • 6 Department of Infectious Diseases and Tropical Medicine, Jagiellonian University Medical College, Krakow, Poland.
  • 7 Université Paris Cité, INSERM U1016, CNRS UMR8104, Institut Cochin, Paris, France.
  • 8 CHU d'Orléans, Orléans, France.
  • 9 Université d'Orléans, LI²RSO, Orléans, France.
  • 10 Service des Maladies Infectieuses, CHU St-Pierre, Université Libre de Bruxelles (ULB), Brussels, 1000, Belgium.
  • 11 Laboratory of Molecular Virology, The International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
  • 12 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland. k.a.pyrc@uj.edu.pl.
  • 13 Laboratory of Experimental Virology, Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands. a.o.pasternak@amsterdamumc.nl.
  • 14 Service of Molecular Virology, Department of Molecular Biology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium. carine.vanlint@ulb.be.
  • 15 Laboratory of Molecular Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland. anna.kula-pacurar@uj.edu.pl.
  • # Contributed equally.
PMID: 40021667 DOI: 10.1038/s41467-025-57290-y
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.

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