title: Inhibition of HIV-1 maturation via drug association with the viral Gag protein in immature HIV-1 particles.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Huang
authors.forename: David L
authors.initials: DL
authors.lastname: Hachey
authors.forename: Chin Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Christopher
authors.initials: C
authors.lastname: Aiken
mesh_terms: D002460:Cell Line; D015683:Gene Products, gag / Q000187:drug effects / Q000502:physiology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D014771:Virion / Q000502:physiology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D015683:Gene Products, gag