In vitro analysis of human immunodeficiency virus type 1 resistance to nevirapine and fitness determination of resistant variants.

Published

Journal Article

Nevirapine-resistant variants were generated by serial passages in MT-2 cells in the presence of increasing drug concentrations. In passage 5, mutations V106A, Y181C and G190A were detected in the global population, associated with a 100-fold susceptibility decrease. Sequence analysis of biological clones obtained from passage 5 and subsequent passages showed that single mutants, detected in first passages, were progressively replaced in passage 15 by double mutants, correlating with a 500-fold increase in phenotypic resistance. Fitness determination of single mutants confirmed that, in the presence of nevirapine, every variant was more fit than wild-type with a fitness order Y181C>V106A>G190A>wild-type. Unexpectedly, in the absence of the drug, the Y181C resistant mutant was more fit than wild-type, with a fitness gradient Y181C>wild-type >G106A>or=V190A. Using a molecular clone in which the Y181C mutation was introduced by in vitro mutagenesis, the greater fitness of the Y181C mutant was confirmed in new competition cultures. These data exemplify the role of resistance mutations on virus phenotype but also on virus evolution leading, occasionally, to resistant variants fitter than the wild-type in the absence of the drug.

Full Text

Duke Authors

Cited Authors

  • Iglesias-Ussel, MD; Casado, C; Yuste, E; Olivares, I; López-Galíndez, C

Published Date

  • January 2002

Published In

Volume / Issue

  • 83 / Pt 1

Start / End Page

  • 93 - 101

PubMed ID

  • 11752705

Pubmed Central ID

  • 11752705

Electronic International Standard Serial Number (EISSN)

  • 1465-2099

International Standard Serial Number (ISSN)

  • 0022-1317

Digital Object Identifier (DOI)

  • 10.1099/0022-1317-83-1-93

Language

  • eng