PRJNA433660
Capsid-CPSF6 interaction as opposed to nuclear architecture dictates intranuclear HIV-1 localization and integration site selection
Image-based studies suggest nuclear architecture dictates HIV-1 integration site selection. Here we investigated the early phase of HIV-1 infection in transformed and primary cells using multiple orthologous approaches including viral imaging, integration site mapping, and intranuclear localization of preferred gene targets. Our multimodal approach demonstrates that under normal infection conditions, HIV-1 disperses throughout the nucleus for integration into transcriptionally active gene-dense regions. Loss of interaction with the viral capsid host cofactor cleavage and polyadenylation specificity factor 6 (CPSF6), however, dramatically altered virus localization towards the nuclear periphery and integration into transcriptionally inactive lamina-associated heterochromatin. By contrast, the integrase-binding cofactor lens epithelium-derived growth factor/p75 did not play a significant role in HIV-1 intranuclear localization. We conclude that the CPSF6-capsid interaction, and not nuclear architecture, plays a dominant role in viral intranuclear trafficking. CPSF6 directs HIV-1 preintegration complexes away from heterochromatin at the nuclear periphery towards gene-dense euchromatin located throughout the nucleus.