Integrase Interacts with Nucleoporin NUP153 To Mediate the Nuclear Import of Human Immunodeficiency Virus Type 1

ABSTRACT The ability to traverse an intact nuclear envelope and productively infect nondividing cells is a salient feature of human immunodeficiency virus type 1 (HIV-1) and other lentiviruses, but the viral factors and mechanism of nuclear entry have not been defined. HIV-1 integrase (IN) is implicated to play a role in the nuclear import of the virus, but the cellular pathway for IN trafficking and the role of IN in mediating the nuclear import of viral particles are unknown. Using a semipermeabilized cell assay, we observed that the nuclear import of IN was not the result of passive diffusion but occurred independently of cytosolic factors, metabolic energy, and the classical receptor-mediated, Ran-dependent import pathways. To determine if IN enters the nucleus by interacting with the nucleopore complex (NPC), we found that IN bound directly with the FxFG-rich C-terminal domain of nucleoporin 153 (NUP153C). When added in excess to the import assay, NUP153C inhibited the nuclear import of IN. Known binding partners of NUP153C competed with IN for binding with NUP153 and also inhibited the nuclear import of IN. In cultured cells, overexpression of NUP153C reduced the infectivity of an HIV-derived vector by interfering with the nuclear translocation of the viral cDNA. These results support a functional role for the IN-NUP153 interaction in HIV-1 replication and suggest that HIV-1 subviral particles gain access to the nucleus by interacting directly with the NPC via the binding of particle-associated IN to NUP153C.

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