title: A single polymorphism in HIV-1 subtype C SP1 is sufficient to confer natural resistance to the maturation inhibitor bevirimat.
abstract: 3-O-(3',3'-Dimethylsuccinyl) betulinic acid (DSB), also known as PA-457, bevirimat (BVM), or MPC-4326, is a novel HIV-1 maturation inhibitor. Unlike protease inhibitors, BVM blocks the cleavage of the Gag capsid precursor (CA-SP1) to mature capsid (CA) protein, resulting in the release of immature, noninfectious viral particles. Despite the novel mechanism of action and initial progress made in small-scale clinical trials, further development of bevirimat has encountered unexpected challenges, because patients whose viruses contain genetic polymorphisms in the Gag SP1 (positions 6 to 8) protein do not generally respond well to BVM treatment. To better define the role of amino acid residues in the HIV-1 Gag SP1 protein that are involved in natural polymorphisms to confer resistance to the HIV-1 maturation inhibitor BVM, a series of Gag SP1 chimeras involving BVM-sensitive (subtype B) and BVM-resistant (subtype C) viruses was generated and characterized for sensitivity to BVM. We show that SP1 residue 7 of the Gag protein is a primary determinant of SP1 polymorphism-associated drug resistance to BVM.
authors.affiliation: Department of Biology and Microbiology, South Dakota State University, Brookings, South Dakota 57007, USA.
authors.forename: Wuxun
authors.initials: W
authors.lastname: Lu
authors.forename: Karl
authors.initials: K
authors.lastname: Salzwedel
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Suvobrata
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Eric O
authors.initials: EO
authors.lastname: Freed
authors.forename: Carl T
authors.initials: CT
authors.lastname: Wild
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D053978:Pentacyclic Triterpenes; D011110:Polymorphism, Genetic / Q000235:genetics*; D014315:Triterpenes / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics*; D000094062:Betulinic Acid
chemical_list: D019380:Anti-HIV Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; D000094062:Betulinic Acid