HIV-1 Gag metamorphoses inside each virion, from an immature lattice that forms during viral production to a mature capsid that drives infection. Here we show that the immature lattice is required to concentrate the cellular metabolite inositol hexakisphosphate (IP6) into virions to catalyze mature capsid assembly. Disabling the ability of HIV-1 to enrich IP6 does not prevent immature lattice formation or production of the virus. However, without sufficient IP6 molecules inside each virion, HIV-1 can no longer build a stable capsid and fails to become infectious. IP6 cannot be replaced by other inositol phosphate (IP) molecules, as substitution with other IPs profoundly slows mature assembly kinetics and results in virions with gross morphological defects. Our results demonstrate that while HIV-1 can become independent of IP6 for immature assembly, it remains dependent upon the metabolite for mature capsid formation.
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| http://dx.doi.org/10.1038/s41594-022-00887-4 | DOI Listing |
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Article Synopsis
- HIV-1 inhibitors Bevirimat (BVM) and Lenacapavir (LEN) work by blocking the production and maturation of infectious viral particles, but their exact mechanisms were not well understood due to limited structural data.
- Using perforated virus-like particles from mammalian cells, researchers utilized cryo-electron microscopy to achieve high-resolution structures of HIV-1 with BVM and LEN, marking the first detailed view of these inhibitors interacting with the immature virus.
- The study revealed how BVM binds to the Gag lattice and showed that LEN not only targets the mature capsid but also the immature lattice, causing significant changes in the capsid protein and Gag structure, which might influence the virus's maturation process.
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