A stable immature lattice packages IP₆ for HIV capsid maturation

Area of Science:

• Virology
• Structural Biology
• Molecular Biology

Background:

• HIV virion assembly involves immature Gag hexamer lattices that mature into capsid structures post-release.
• Protease-mediated Gag cleavage triggers HIV maturation, disassembling the immature lattice and assembling the mature capsid.
• Inositol hexakisphosphate (IP6) and maturation inhibitors (MIs) stabilize immature Gag lattices, but IP6 promotes maturation while MIs inhibit it.

Purpose of the Study:

• To investigate the evolutionary constraints on HIV immature lattice stability.
• To understand the interplay between IP6, MIs, and Gag hexamer stability in HIV maturation.
• To explore strategies for enhancing the antiviral potency of MIs.

Main Methods:

• Analysis of replication-deficient HIV mutants with altered IP6 recruitment.
• Treatment of mutant viruses with the maturation inhibitor PF46396 (PF96).
• Identification of second-site compensatory mutations affecting lattice stability and IP6 incorporation.

Main Results:

• Reduced IP6 recruitment in mutant viruses correlated with increased infectivity upon PF96 treatment or compensatory mutations.
• Both PF96 and second-site mutations stabilized the immature lattice and restored IP6 incorporation.
• Immature lattice stability and IP6 binding were found to be interdependent.

Conclusions:

• HIV maintains a delicate balance in immature lattice stability to ensure IP6 packaging without hindering maturation.
• The observed IP6 dependence suggests a potential therapeutic strategy.
• Developing MIs that compete with IP6 for Gag hexamer binding could significantly improve their antiviral efficacy against HIV.