biostudies-literatureLee KIntramural NIH HHSNIAID NIH HHSNCI NIH HHS221-33https://www.ebi.ac.uk/biostudies/studies/S-EPMC2841689biostudies-literatureUnknown7(3)HIV-1 replication requires transport of nascent viral DNA and associated virion proteins, the retroviral preintegration complex (PIC), into the nucleus. Too large for passive diffusion through nuclear pore complexes (NPCs), PICs use cellular nuclear transport mechanisms and nucleoporins (NUPs), the NPC components that permit selective nuclear-cytoplasmic exchange, but the details remain unclear. Here we identify a fragment of the cleavage and polyadenylation factor 6, CPSF6, as a potent inhibitor of HIV-1 infection. When enriched in the cytoplasm, CPSF6 prevents HIV-1 nuclear entry by targeting the viral capsid (CA). HIV-1 harboring the N74D mutation in CA fails to interact with CPSF6 and evades the nuclear import restriction. Interestingly, whereas wild-type HIV-1 requires NUP153, N74D HIV-1 mimics feline immunodeficiency virus nuclear import requirements and is more sensitive to NUP155 depletion. These findings reveal a remarkable flexibility in HIV-1 nuclear transport and highlight a single residue in CA as essential in regulating interactions with NUPs.Cell host & microbeFlexible use of nuclear import pathways by HIV-1.PMC2841689R37 CA089441CA089441AI52014R01 CA089441AI033303ZIA BC010487-07R01 AI063987AI033856R37 AI033303R01 AI049131R01 AI052014AI076094R01 AI033856R21 AI076094AI49131AI063987Oztop ITaniuchi IUnutmaz DAmbrose ZYuen WShelton KBaumann JGJulias JGLee KVandegraaff NEngelman AMartin TDTakemura TLi YLittman DRWang RMulky ACoffin JMSodroski JKewalRamani VNHughes SHfalseFlexible use of nuclear import pathways by HIV-1.HIV-1 replication requires transport of nascent viral DNA and associated virion proteins, the retroviral preintegration complex (PIC), into the nucleus. Too large for passive diffusion through nuclear pore complexes (NPCs), PICs use cellular nuclear transport mechanisms and nucleoporins (NUPs), the NPC components that permit selective nuclear-cytoplasmic exchange, but the details remain unclear. Here we identify a fragment of the cleavage and polyadenylation factor 6, CPSF6, as a potent inhibitor of HIV-1 infection. When enriched in the cytoplasm, CPSF6 prevents HIV-1 nuclear entry by targeting the viral capsid (CA). HIV-1 harboring the N74D mutation in CA fails to interact with CPSF6 and evades the nuclear import restriction. Interestingly, whereas wild-type HIV-1 requires NUP153, N74D HIV-1 mimics feline immunodeficiency virus nuclear import requirements and is more sensitive to NUP155 depletion. These findings reveal a remarkable flexibility in HIV-1 nuclear transport and highlight a single residue in CA as essential in regulating interactions with NUPs.2010-01-01T00:00:00Z2010 Mar2020-10-29T14:26:35Z2019-03-27T00:29:32ZS-EPMC28416892022766510.1016/j.chom.2010.02.007