Figure 7.

Conceptual model of HIV-1 nuclear import in T cells

In the cytosol, the intact cone-shaped HIV-1 capsid encasing the viral genome travels along microtubules (MT) toward the nuclear periphery (I), where it encounters NUP358 bound to the cytoplasmic face of NPCs and docks to the NPC with the narrow CA pentamer-rich end (II). Subsequently, the capsid penetrates into the central channel (III). Superimposition of the mature HIV-1 capsid as determined from intact virions (Mattei et al., 2016) onto the in cellulo structural model of the NPC from infected cells (this study) reveals that the diameter of the NPC central channel is sufficiently wide for the transport of intact HIV-1 capsid. Side view (left) and top view (right) are shown as inset (III). The intact HIV-1 capsid translocates into the nucleus (IV.). Although we cannot formally exclude that the CA lattice is perturbed during transport, all capsids observed inside of the central channel were cone-shaped. Upon departure from the NPC central channel, capsids encounter NUP153 and CPSF6. When CPSF6 binding is perturbed, the capsid uncoats and releases the genome at the NPC nuclear basket region (V). When CPSF6 is available for interaction with the CA lattice, uncoating occurs deeper in the nucleoplasm (Burdick et al., 2020). In both cases (V and VI), the viral genome is released and integration into the host genome occurs close to the site of release.