As a lentivirus, HIV is capable of infecting non-dividing cells. For decades it has been understood that HIV must be able to deliver its genetic material across the nuclear envelope in order to establish infection. As the gatekeeper between the cytoplasm and the nucleus, the nuclear pore complex (NPC) represents an obvious entry point. During normal cellular function, the NPC controls nucleocytoplasmic transport by establishing a ‘diffusion barrier’ at the centre of the pore. Often described as a ‘mesh’ or ‘filter’, the diffusion barrier is formed by intrinsically-disordered nucleoporin domains which project into the central pore. Critically, these domains are enriched for phenylalanine-glycine (FG) dipeptide motifs that cause them to form a liquid-liquid phase separation which typically prevents the passive diffusion of molecules greater than ~25 kDa. Larger cargoes can be escorted across the nuclear pore by the action of karyopherins – chaperone proteins which can cross the diffusion barrier by virtue of their weak, multivalent, and specific interactions with the FG motifs.
Recent studies have shown that the HIV capsid also possesses a conserved FG-binding pocket on it surface. Indeed, it is this same site that is targeted so successfully by the first-in-class anticapsid drug, lenacapavir. This ‘FG-pocket’ grants the capsid similar biophysical properties to the karyopherins, thereby licensing the capsid for nuclear entry without the need of chaperones. The karyopherin mimicry model explains how a structure as large as the HIV core can penetrate the nucleus despite being greater than 10,000 times the diffusion limit of the nuclear pore.