The role of CPSF6 in HIV-1 infection

Division Of Basic Sciences - Nci

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Abstract

We are seeking to define the route that HIV-1 takes to the nucleus: the cell factors it interacts with and how it interacts with these factors. We are examining whether CPSF6 normally interacts with HIV-1 CA in the cytoplasm and whether this interaction is important for nuclear entry of the virus. Within the nucleus, we find that the HIV-1 pre-integration complex interacts with CPSF6, and this interaction regulates HIV-1 integration in the host cell chromatin. Notably, we find that by interacting with CPSF6, HIV-1 is first directed to speckles after entering the nucleus and prior to integration. Nuclear speckles colocalize with regions of chromatin that HIV-1 preferentially integrates. Thus, we and others hypothesize that HIV-1 co-opted CPSF6 to access regions of chromatin that are broadly transcriptionally active due to their proximity to nuclear speckles. A companion effort has identified cytoplasmic and nuclear host factors that affect CPSF6-trafficking of the HIV-1 to nuclear speckles. In particular, we have been examining the role of DDX3X, and RNA-interacting DEAD box helicase protein, in regulating HIV-1 access to CPSF6 bodies. Removal of this protein prevents HIV-1 from efficiently accessing nuclear speckles. Our data and data from other groups suggest that HIV-1 potentially interacts with a series of biomolecular condensates while trafficking from cytoplasm to nucleus.