The HIV Preintegration Complex (PIC) mediates the integration of the viral reverse transcript into host cell chromosomes. The HIV core is composed of a shell of capsid protein that encases the viral RNA together with reverse transcriptase and integrase enzymes. Reverse transcription occurs within the viral core, and nicking of the viral DNA ends by integrase converts the reverse transcription complex into the integration-competent PIC. After circumventing the nuclear pore complex, the core traffics to interior regions of the nucleus for uncoating and integration. Integration into host chromosomes is non-random, and interactions between the capsid and integrase proteins with cognate host factors guides the core to transcriptionally active chromatin. The interaction of capsid with alternative polyadenylation host protein CPSF6 is required for cores to move beyond the nuclear rim, where they eventually congregate with nuclear speckles for integration into nearby speckle-associated domains (SPADs) of chromatin. Interactions between integrase and transcriptional coactivator LEDGF/p75 direct integration into the mid-regions of active genes. Recent work has clarified that both CPSF6 and LEDGF/p75 possess liquid-liquid phase separation activity and that these activities can impact their roles as integration cofactors. Completion of reverse transcription can aid core dissolution or uncoating to reveal chromatin to the PIC for integrase-mediated integration of viral DNA.
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