A Hybrid Gag Lattice as a Structural Intermediate in HIV-1 Maturation.

Area of Science:

• Structural Biology
• Virology
• Biochemistry

Background:

• HIV-1 maturation is essential for viral infectivity, converting the immature Gag lattice to a mature capsid.
• The precise structural pathway from immature to mature capsid remains incompletely understood.

Purpose of the Study:

• To elucidate the structural intermediates and mechanisms governing HIV-1 capsid maturation.
• To identify the role of specific lattice architectures and molecules in this process.

Main Methods:

• Single-particle cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET).
• Reconstitution of viral assemblies and analysis of virus-like particles (VLPs).
• Molecular dynamics simulations.

Main Results:

• A distinct hybrid lattice intermediate was identified, featuring mature N-terminal domains and immature C-terminal domains of the capsid protein (CA).
• This hybrid lattice binds three myo-inositol hexakisphosphate (IP6) molecules per CA-SP1 hexamer and is stabilized by IP6.
• Hybrid regions were observed within immature lattices in native VLPs, suggesting localized remodeling and partial disassembly/reassembly during maturation.

Conclusions:

• The hybrid lattice represents a crucial on-pathway intermediate in HIV-1 maturation.
• Disruption of hybrid-specific contacts impairs infectivity and mature capsid formation.
• A model is proposed where localized remodeling, partial disassembly/reassembly, and IP6 dynamics drive maturation from immature to mature states, highlighting the hybrid lattice as a therapeutic target.