Mechanistic Insights into HIV-1 Capsid Interactions with CPSF6

The process of HIV-1 entering the nucleus of a host cell is a multi-step journey that begins with the docking of the viral capsid at the nuclear pore complex (NPC). During this critical stage, the capsid interacts with various cellular host factors, one of which is cleavage and polyadenylation specificity factor 6 (CPSF6). This factor plays a pivotal role in facilitating the efficient nuclear entry and integration of the virus.

Initial experimental observations suggest that nucleoporins such as NUP153 first engage the capsid, followed by the binding and subsequent oligomerization of CPSF6 during later stages of nuclear import. Nonetheless, the underlying mechanism by which CPSF6 binds to the capsid and subsequently forms oligomers has not been well elucidated.

In an effort to fill this knowledge gap, researchers have developed bottom-up coarse-grained (CG) models that simulate the CPSF6 binding and oligomerization process on the HIV-1 capsid. The simulations indicate that CPSF6 assembles into a mesh-like coating encircling the capsid, aligning with experimental findings. Moreover, the simulations reveal that CPSF6 binding is contingent on the intrinsic curvature of the capsid lattice.

Lastly, the researchers investigate the impact of disrupting CPSF6-CPSF6 interactions on binding, oligomerization dynamics, and curvature dependence. These findings collectively offer novel mechanistic insights into the role of CPSF6 in regulating HIV-1 nuclear entry.