CPSF6 Defines a Conserved Capsid Interface that Modulates HIV-1 Replication

The hiv-1 genome enters cells inside a shell comprised of capsid (ca) protein. variation in ca sequence alters hiv-1 infectivity and escape from host restriction factors. however,apart from the cyclophilin a-binding loop,ca has no known interfaces with which to interact with cellular cofactors. here we describe a novel protein-protein interface in the n-terminal domain of hiv-1 ca,determined by x-ray crystallography,which mediates both viral restriction and host cofactor dependence. the interface is highly conserved across lentiviruses and is accessible in the context of a hexameric lattice. mutation of the interface prevents binding to and restriction by cpsf6-358,a truncated cytosolic form of the rna processing factor,cleavage and polyadenylation specific factor 6 (cpsf6). furthermore,mutations that prevent cpsf6 binding also relieve dependence on nuclear entry cofactors tnpo3 and ranbp2. these results suggest that the hiv-1 capsid mediates direct host cofactor interactions to facilitate viral infection.