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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

  1. Author:
    Kleinpeter,Alex
    Zhu, Yanan
    Mallery, Donna L
    Ablan,Sherimay
    Chen, Long
    Hardenbrook, Nathan
    Saiardi, Adolfo
    James, Leo C
    Zhang, Peijun
    Freed,Eric

  2. Author Address

    Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA. Electronic address: https://twitter.com/AlexKleinpeter., Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK., MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK., Laboratory for Molecular Cell Biology, University College London, London, UK. Electronic address: https://twitter.com/SaiardiLab., MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: https://twitter.com/JamesLab9., Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK; Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford OX3 7BN, UK., Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702-1201, USA. Electronic address: efreed@nih.gov.,
    1. Year: 2023
    2. Date: Apr 01
    3. Epub Date: 2023 04 01
  2. Journal: Journal of Molecular Biology
    1. 435
    2. 11
    3. Pages: 168037
  4. Type of Article: Article
  5. Article Number: 168037
  1. Abstract:

    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. Copyright © 2023 Elsevier Ltd. All rights reserved.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.jmb.2023.168037
  3. PMID: 37330292
  4. View record in Web of Science®
  5. WOS: 001033205800001
  6. PII : S0022-2836(23)00093-1

Library Notes

  1. Fiscal Year: FY2022-2023
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