Journal
NATURE MICROBIOLOGY
Volume 4, Issue 11, Pages 1840-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41564-019-0575-6
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Funding
- Labex EpiGenMed, an 'Investissements d'avenir' program [ANR-10-LABX-12-01]
- ATIP-Avenir program
- Sidaction
- ANRS (Agence Nationale de Recherche sur le Sida)
- CNRS (Centre National de Recherche Scientifique)
- French Ministry of Higher Education and Research
- REDSAIM project-Pacte metropolitain d'innovation de Montpellier
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The initial steps of HIV replication in host cells prime the virus for passage through the nuclear pore and drive the establishment of a productive and irreparable infection(1,2). The timely release of the viral genome from the capsid-referred to as uncoating-is emerging as a critical parameter for nuclear import, but the triggers and mechanisms that orchestrate these steps are unknown. Here, we identify beta-karyopherin Transportin-1 (TRN-1) as a cellular co-factor of HIV-1 infection, which binds to incoming capsids, triggers their uncoating and promotes viral nuclear import. Depletion of TRN-1, which we characterized by mass spectrometry, significantly reduced the early steps of HIV-1 infection in target cells, including primary CD4+ T cells. TRN-1 bound directly to capsid nanotubes and induced dramatic structural damage, indicating that TRN-1 is necessary and sufficient for uncoating in vitro. Glycine 89 on the capsid protein, which is positioned within a nuclear localization signal in the cyclophilin A-binding loop, is critical for engaging the hydrophobic pocket of TRN-1 at position W730. In addition, TRN-1 promotes the efficient nuclear import of both viral DNA and capsid protein. Our study suggests that TRN-1 mediates the timely release of the HIV-1 genome from the capsid protein shell and efficient viral nuclear import.
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