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The Effect of Inositol Hexakisphosphate on HIV-1 Particle Production and Infectivity can be Modulated by Mutations that Affect the Stability of the Immature Gag Lattice
Journal article   Open access   Peer reviewed

The Effect of Inositol Hexakisphosphate on HIV-1 Particle Production and Infectivity can be Modulated by Mutations that Affect the Stability of the Immature Gag Lattice

Alex B. Kleinpeter, Yanan Zhu, Donna L. Mallery, Sherimay D. Ablan, Long Chen, Nathan Hardenbrook, Adolfo Saiardi, Leo C. James, Peijun Zhang and Eric O. Freed
Journal of molecular biology, Vol.435(11), pp.168037-168037
06/01/2023
DOI: 10.1016/j.jmb.2023.168037
PMCID: PMC10544863
PMID: 37330292
url
https://doi.org/10.1016/j.jmb.2023.168037View
Published (Version of record) Open Access

Abstract

[Display omitted] •IP6 depletion in virus-producer cells restores virion infectivity to an HIV-1 Gag mutantwith a hyperstable six-helix bundle.•Cryo-ET confirms IP6-independent assembly of the K158A/K227A (KAKA) HIV-1 CA mutant.•Addition of KAKA to M4L/T8I restores CA-SP1 processing without restoring infectivity. The assembly of an HIV-1 particle begins with the construction of a spherical lattice composed of hexamer subunits of the Gag polyprotein. The cellular metabolite inositol hexakisphosphate (IP6) binds and stabilizes the immature Gag lattice via an interaction with the six-helix bundle (6HB), a crucial structural feature of Gag hexamers that modulates both virus assembly and infectivity. The 6HB must be stable enough to promote immature Gag lattice formation, but also flexible enough to be accessible to the viral protease, which cleaves the 6HB during particle maturation. 6HB cleavage liberates the capsid (CA) domain of Gag from the adjacent spacer peptide 1 (SP1) and IP6 from its binding site. This pool of IP6 molecules then promotes the assembly of CA into the mature conical capsid that is required for infection. Depletion of IP6 in virus-producer cells results in severe defects in assembly and infectivity of wild-type (WT) virions. Here we show that in an SP1 double mutant (M4L/T8I) with a hyperstable 6HB, IP6 can block virion infectivity by preventing CA-SP1 processing. Thus, depletion of IP6 in virus-producer cells markedly increases M4L/T8I CA-SP1 processing and infectivity. We also show that the introduction of the M4L/T8I mutations partially rescues the assembly and infectivity defects induced by IP6 depletion on WT virions, likely by increasing the affinity of the immature lattice for limiting IP6. These findings reinforce the importance of the 6HB in virus assembly, maturation, and infection and highlight the ability of IP6 to modulate 6HB stability.
 HIV-1 assembly HIV-1 maturation Human Immunodeficiency Virus-1 inositol hexakisphosphate (IP6) maturation inhibitors

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