A stable immature lattice packages IP₆ for HIV capsid maturation.

Abstract

HIV virion assembly begins with the construction of an immature lattice consisting of Gag hexamers. Upon virion release, protease-mediated Gag cleavage leads to a maturation event in which the immature lattice disassembles and the mature capsid assembles. The cellular metabolite inositiol hexakisphosphate (IP₆) and maturation inhibitors (MIs) both bind and stabilize immature Gag hexamers, but whereas IP₆ promotes virus maturation, MIs inhibit it. Here we show that HIV is evolutionarily constrained to maintain an immature lattice stability that ensures IP₆ packaging without preventing maturation. Replication-deficient mutant viruses with reduced IP₆ recruitment display increased infectivity upon treatment with the MI PF46396 (PF96) or the acquisition of second-site compensatory mutations. Both PF96 and second-site mutations stabilise the immature lattice and restore IP₆ incorporation, suggesting that immature lattice stability and IP₆ binding are interdependent. This IP₆ dependence suggests that modifying MIs to compete with IP₆ for Gag hexamer binding could substantially improve MI antiviral potency.