Two structural switches in HIV-1 capsid regulate capsid curvature and host factor binding

Area of Science:

• Structural biology
• Virology
• Molecular biology

Background:

• The mature human immunodeficiency virus type 1 (HIV-1) capsid is essential for protecting the viral genome and facilitating nuclear import.
• The capsid protein (CA) forms a lattice of hexamers and pentamers, interacting dynamically with host factors like Nup153, CPSF6, and Sec24C.
• Key questions remain regarding CA assembly, curvature modulation of host interactions, and coordination of cofactor binding.

Purpose of the Study:

• To elucidate the structural basis of HIV-1 capsid assembly and host protein interactions.
• To understand how CA oligomerization and lattice curvature influence binding to cellular factors.
• To reveal the mechanisms coordinating multiple cofactor interactions at a single CA binding site.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures.
• Structures of CA pentamers and hexamers from conical CA-IP6 polyhedra were resolved to approximately 3 Å resolution.
• Cryo-EM structures were obtained for hexamers across various lattice curvatures and pentamer contact numbers, with and without host protein peptides.

Main Results:

• The study determined the ~3 Å resolution cryo-EM structures of mature HIV-1 CA pentamers and hexamers.
• Structures revealed CA hexamers associated with different lattice curvatures and varying numbers of pentamer contacts.
• Comparison of structures identified two key structural switches in CA that modulate host peptide binding based on lattice curvature and oligomeric state (pentameric vs. hexameric).

Conclusions:

• The conical HIV-1 capsid exhibits distinct host-protein binding properties across its surface, influenced by lattice curvature and CA oligomeric state.
• These differential binding properties, mediated by structural switches, likely play a crucial role in facilitating viral cell entry.
• The conical morphology may confer an evolutionary advantage by enabling dynamic and position-specific interactions with host factors during infection.