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In vitro development of resistance to human immunodeficiency virus protease inhibitor GW640385

P J Yates1, R Hazen, M St Clair

  • 1UK Virology, GlaxoSmithKline Inc., Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom. pjy29430@gsk.com

Antimicrobial Agents and Chemotherapy
|February 24, 2006
PubMed

Insights

Researchers studied in vitro resistance to GW640385, a human immunodeficiency virus type 1 protease inhibitor. They identified key amino acid substitutions in protease and Gag that confer significant drug resistance, impacting viral replication.

Area of Science:

  • Virology
  • Drug Resistance Studies
  • Molecular Biology

Background:

  • Human immunodeficiency virus type 1 (HIV-1) protease inhibitors are crucial in antiretroviral therapy.
  • Emergence of drug-resistant viral strains necessitates continuous development of new inhibitors.
  • GW640385 is a novel HIV-1 protease inhibitor targeting viral maturation.

Purpose of the Study:

  • To investigate the in vitro development of resistance to the HIV-1 protease inhibitor GW640385.
  • To characterize the genetic mutations in HIV-1 protease and Gag associated with GW640385 resistance.
  • To assess the impact of specific mutations on viral replication capacity.

Main Methods:

  • In vitro selection of GW640385-resistant HIV-1 variants.
  • Genotypic analysis of protease and Gag genes from resistant viral isolates.
  • Phenotypic characterization of viral replication capacity.

Main Results:

  • Two distinct resistant variants were identified: one with <4-fold resistance (Q58E/A71V protease, P452K Gag) and another with >50-fold resistance (L10F/G16E/E21K/A28S/M46I/F53L/A71V protease, L449F/P453T Gag).
  • The A28S substitution within the protease gene was found to significantly reduce viral replication capacity.
  • Multiple amino acid substitutions in both protease and Gag contributed to high-level resistance.

Conclusions:

  • In vitro resistance to GW640385 can develop through specific amino acid substitutions in HIV-1 protease and Gag.
  • The identified mutations provide insight into the resistance mechanisms of this new protease inhibitor.
  • The reduced replication capacity associated with the A28S mutation suggests a potential fitness cost for resistance development.

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