Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles.

Published

Journal Article

The small molecule 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB) potently inhibits human immunodeficiency virus, type 1 (HIV-1) replication by interfering with proteolytic cleavage of the viral Gag protein at a specific site. Here we have demonstrated that the antiviral mechanism involves the association of DSB with Gag at a 1:1 stoichiometry within immature HIV-1 particles. The binding was specific, as mutations in Gag that confer resistance to DSB inhibited the association, which could be competed by DSB but not by the inactive compound betulinic acid. The addition of DSB to purified immature viral cores inhibited the cleavage of Gag at the CA-SP1 junction in vitro, thus reproducing the effect of the drug when present during maturation of HIV-1 particles. Based on these findings, we propose a model in which a trimer of DSB associates with the CA-SP1 junction of adjacent subunits within the Gag polymer. The model may explain the ability of highly similar compounds to specifically target the seemingly unrelated steps of HIV-1 maturation and virus entry.

Full Text

Duke Authors

Cited Authors

  • Zhou, J; Huang, L; Hachey, DL; Chen, CH; Aiken, C

Published Date

  • December 23, 2005

Published In

Volume / Issue

  • 280 / 51

Start / End Page

  • 42149 - 42155

PubMed ID

  • 16251182

Pubmed Central ID

  • 16251182

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M508951200

Language

  • eng

Conference Location

  • United States