Hierarchical assembly governs TRIM5α recognition of HIV-1 and retroviral capsids

TRIM5 alpha is a restriction factor that senses incoming retrovirus cores through an unprecedented mechanism of nonself recognition. TRIM5 alpha assembles a hexagonal lattice that avidly binds the capsid shell, which surrounds and protects the virus core. The extent to which the TRIM lattice can cover the capsid and how TRIM5 alpha directly contacts the capsid surface have not been established. Here, we apply cryo-electron tomography and subtomogram averaging to determine structures of TRIM5 alpha bound to recombinant HIV-1 capsid assemblies. Our data support a mechanism of hierarchical assembly, in which a limited number of basal interaction modes are successively organized in increasingly higher-order structures that culminate in a TRIM5 alpha cage surrounding a retroviral capsid. We further propose that cage formation explains the mechanism of restriction and provides the structural context that links capsid recognition to ubiquitin-dependent processes that disable the retrovirus.