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The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals. [ABSTRACT FROM AUTHOR]

The article presents a study which showed that HIV is evolutionarily constrained to maintain an immature lattice stability that ensures IP6 packaging without preventing maturation. Topics discussed include interdependence of IP6 binding and immature lattice stability, effects of treatment with the MI PF96, and IP6 incorporation as the key feature linking immature lattice stability to virion maturation and infectivity.

HIV-1 hijacks host proteins to promote infection. Here we show that HIV is also dependent upon the host metabolite inositol hexakisphosphate (IP 6 ) for viral production and primary cell replication. HIV-1 recruits IP 6 into virions using two lysine rings in its immature hexamers. Mutation of either ring inhibits IP 6 packaging and reduces viral production. Loss of IP 6 also results in virions with highly unstable capsids, leading to a profound loss of reverse transcription and cell infection. Replacement of one ring with a hydrophobic isoleucine core restores viral production, but IP 6 incorporation and infection remain impaired, consistent with an independent role for IP 6 in stable capsid assembly. Genetic knockout of biosynthetic kinases IPMK and IPPK reveals that cellular IP 6 availability limits the production of diverse lentiviruses, but in the absence of IP 6 , HIV-1 packages IP 5 without loss of infectivity. Together, these data suggest that IP 6 is a critical cofactor for HIV-1 replication., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The stability of the HIV-1 capsid and the spatiotemporal control of its disassembly, a process called uncoating, need to be finely tuned for infection to proceed. Biochemical methods for measuring capsid lattice disassembly in bulk are unable to resolve intermediates in the uncoating reaction. We have developed a single-particle fluorescence microscopy method to follow the real-time uncoating kinetics of authentic HIV capsids in vitro . The assay utilizes immobilized viral particles that are permeabilized with the a pore-former protein, and is designed to (1) detect the first defect of the capsid by the release of a solution phase marker (GFP) and (2) visualize the disassembly of the capsid over time by "painting" the capsid lattice with labeled cyclophilin A (CypA), a protein that binds weakly to the outside of the capsid. This novel assay allows the study of dynamic interactions of molecules with hundreds of individual capsids as well as to determine their effect on viral capsid stability, which provides a powerful tool for dissecting uncoating mechanisms and for the development of capsid-binding drugs., Competing Interests: Competing interestsThere are no conflicts of interest or competing interest., (©Copyright Márquez et al.)