Fig. 8.

Model of C-A1 mode of action. (1) HIV-1 uncoating in the cytoplasm and at the nuclear pore. (2) A partially disassembled core is transported across the nuclear pore, reaching the nuclear basket where Nup153 helps maintaining the PIC structure. (3) The PIC is delivered onto chromatin domains rich in actively transcribing genes by binding to CPSF6. Some of these domains are in proximity of the nuclear pores [80, 81]. Uncoating is completed, possibly by TNPO3; capsid and CPSF6 are dissociated from the PIC, which binds to LEDGF to integrate in proximity of genes. (4) C-A1 perturbs this sequence of events by inducing greater uncoating and by affecting the PIC structure bound to Nup153 (5). When the PIC is delivered onto active chromatin domains, capsid cannot properly dissociate from CPSF6 such that the PIC remains tethered and is unable to proceed to integration (6). Mutant viruses N74D and A105S proceed through a capsid-independent pathway and are insensitive to C-A1