Capsid-CPSF6 Interaction Licenses Nuclear HIV-1 Trafficking to Sites of Viral DNA Integration

HIV-1 integration into the host genome favors actively transcribed genes. Prior work indicated that the nuclear periphery provides the architectural basis for integration site selection, with viral capsid-binding host cofactor CPSF6 and viral integrase-binding cofactor LEDGF/p75 contributing to selection of individual sites. Here, by investigating the early phase of infection, we determine that HIV-1 traffics throughout the nucleus for integration. CPSF6-capsid interactions allow the virus to bypass peripheral heterochromatin and penetrate the nuclear structure for integration. Loss of interaction with CPSF6 dramatically alters virus localization toward the nuclear periphery and integration into transcriptionally repressed lamina-associated heterochromatin, while loss of LEDGF/p75 does not significantly affect intranuclear HIV-1 localization. Thus, CPSF6 serves as a master regulator of HIV-1 intranuclear localization by trafficking viral preintegration complexes away from heterochromatin at the periphery toward gene-dense chromosomal regions within the nuclear interior. [Display omitted] •CA-CPSF6 interaction as opposed to nuclear periphery dictates HIV-1 integration•CPSF6 enables HIV-1 to penetrate the nuclear interior beyond the nuclear periphery•Loss of CPSF6 interaction results in integration at lamina-associated domains•LEDGF/p75 does not play a significant role in intranuclear HIV-1 localization Prior work indicated that the nuclear periphery dictated HIV-1 integration site selection. Using multiple orthologous approaches, Achuthan et al. fail to garner evidence for preferential targeting of the periphery. The interaction between viral capsid and CPSF6 enables HIV-1 to bypass integration into peripheral heterochromatin and penetrate the nuclear structure for integration.