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A Single Polymorphism in HIV-1 Subtype C SP1 Is Sufficient To Confer Natural Resistance to the Maturation Inhibitor Bevirimat

  1. Author:
    Lu, W. X.
    Salzwedel, K.
    Wang, D.
    Chakravarty, S.
    Freed, E. O.
    Wild, C. T.
    Li, F.

  2. Author Address

    [Lu, WX; Wang, D; Li, F] S Dakota State Univ, Dept Biol & Microbiol, Brookings, SD 57007 USA [Lu, WX; Wang, D; Li, F] S Dakota State Univ, Dept Vet & Biomed Sci, Brookings, SD 57007 USA [Salzwedel, K; Wild, CT] Panacos Pharmaceut, Gaithersburg, MD 20877 USA [Chakravarty, S] S Dakota State Univ, Dept Chem & Biochem, Brookings, SD 57007 USA [Freed, EO] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA;Li, F (reprint author), S Dakota State Univ, Dept Vet Sci, Brookings, SD 57007 USA;feng.li@sdstate.edu
    1. Year: 2011
    2. Date: Jul
  2. Journal: Antimicrobial Agents and Chemotherapy
    1. 55
    2. 7
    3. Pages: 3324-3329
  4. Type of Article: Article
  5. ISSN: 0066-4804
  1. 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.

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External Sources

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  2. DOI: 10.1128/aac.01435-10
  3. View record in Web of Science®
  4. WOS: 000291687900034

Library Notes

  1. Fiscal Year: FY2010-2011
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