Impact of Amino Acid Variations in Gag and Protease of HIV Type 1 CRF01_AE Strains on Drug Susceptibility of Virus to Protease Inhibitors

Abstract

Protease (PR) inhibitors (PIs) were designed against subtype B virus of human immunodeficiency virus type 1 (HIV-1), but believed to retain its activity against most of the other subtypes. CRF01_AE PR (AE-PR) contains background mutations that are presumed to alter the drug susceptibility of PR. In addition, amino acid variations found in HIV-1 Gag potentially affect the drug susceptibility or catalytic efficiency of PR. We studied the impact of naturally occurring amino acid substitutions found in AE-PR and CRF01_AE Gag (AE-Gag) on the drug susceptibility of PR to 9 currently available PIs, using the pNL4-3-derived luciferase reporter virus containing AE-Gag and/or AE-PR genes derived from drug treatment-naïve, HIV-1-infected Thai patients. Sequencing analysis revealed that several mutations were detected in deduced amino acid sequences of AE-PR and AE-Gag genes, as compared to these genes of pNL4-3. Drug susceptibility tests revealed that AE-PR showed a variety of susceptibilities to 9 PIs compared with pNL4-3 PR. In addition, AE-Gag significantly reduced the drug susceptibility of AE-PR and pNL4-3 PR. Our results suggest that amino acid variations in AE-PR and AE-Gag play roles in determining the drug susceptibility of CRF01_AE viruses to PIs.