Flexible 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.
Lee
KyeongEun
K
HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.
Ambrose
Zandrea
Z
Martin
Thomas D
TD
Oztop
Ilker
I
Mulky
Alok
A
Julias
John G
JG
Vandegraaff
Nick
N
Baumann
Joerg G
JG
Wang
Rui
R
Yuen
Wendy
W
Takemura
Taichiro
T
Shelton
Kenneth
K
Taniuchi
Ichiro
I
Li
Yuan
Y
Sodroski
Joseph
J
Littman
Dan R
DR
Coffin
John M
JM
Hughes
Stephen H
SH
Unutmaz
Derya
D
Engelman
Alan
A
KewalRamani
Vineet N
VN
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D039223:Cleavage And Polyadenylation Specificity Factor / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014764:Viral Proteins / Q000378:metabolism*
C529056:CPSF6 protein, mouse; D039223:Cleavage And Polyadenylation Specificity Factor; D004279:DNA, Viral; D016655:HIV Core Protein p24; C079377:NUP153 protein, human; C080427:NUP155 protein, human; D028861:Nuclear Pore Complex Proteins; D014764:Viral Proteins