Human Immunodeficiency Virus Type 2 Capsid Protein Mutagenesis Reveals Amino Acid Residues Important for Virus Particle Assembly

Huixin Yang, Nathaniel Talledge, William G. Arndt, Wei Zhang, Louis M. Mansky

Research output: Contribution to journalArticlepeer-review

Abstract

Human immunodeficiency virus (HIV) Gag drives virus particle assembly. The capsid (CA) domain is critical for Gag multimerization mediated by protein–protein interactions. The Gag protein interaction network defines critical aspects of the retroviral lifecycle at steps such as particle assembly and maturation. Previous studies have demonstrated that the immature particle morphology of HIV-2 is intriguingly distinct relative to that of HIV-1. Based upon this observation, we sought to determine the amino acid residues important for virus assembly that might help explain the differences between HIV-1 and HIV-2. To do this, we conducted site-directed mutagenesis of targeted locations in the HIV-2 CA domain of Gag and analyzed various aspects of virus particle assembly. A panel of 31 site-directed mutants of residues that reside at the HIV-2 CA inter-hexamer interface, intra-hexamer interface and CA inter-domain linker were created and analyzed for their effects on the efficiency of particle production, particle morphology, particle infectivity, Gag subcellular distribution and in vitro protein assembly. Seven conserved residues between HIV-1 and HIV-2 (L19, A41, I152, K153, K157, N194, D196) and two non-conserved residues (G38, N127) were found to significantly impact Gag multimerization and particle assembly. Taken together, these observations complement structural analyses of immature HIV-2 particle morphology and Gag lattice organization as well as provide important comparative insights into the key amino acid residues that can help explain the observed differences between HIV immature particle morphology and its association with virus replication and particle infectivity.

Original languageEnglish (US)
Article number167753
JournalJournal of Molecular Biology
Volume434
Issue number19
DOIs
StatePublished - Oct 15 2022

Bibliographical note

Funding Information:
We thank Isaac Angert for comments on the manuscript. This research was supported by NIH grant R01 AI150468 (to L.M.M.). N.T. was supported by NIH grants T32 DA007097, F32 AI150351, and American Cancer Society Postdoctoral Fellowship PF-21-189-01-MPC. W.G.A. was supported by NIH grant NIH T32 AI083196. TEM was carried out in the Characterization Facility, University of Minnesota, which receives partial support from NSF through the MRSEC (DMR-2011401) and NNCI (ECCS-2025124) grants.

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

  • lentivirus
  • maturation
  • morphology
  • retrovirus
  • virus-like particle

PubMed: MeSH publication types

  • Journal Article
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

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