Isolation and Characterization of HIV-1 Isolates Resistant to Oxathiin Carboxanilide Analogues: Evaluation of Variables in the Drug Resistance Selection Process

Abstract

Virus isolates resistant to a variety of structural analogues of oxathiin carboxanilide (UC84) were selected in cell culture and phenotypically and mo!ecularly characterized in order to evaluate the effects of variables in the resistance selection process. The rate of appearance of the resistant viruses and the net loss of sensitivity of the virus isolates to the selecting compound were not dependent on the selective pressure employed against wild-type virus, but were associated with structural features of the compound. Although each of the compounds rapidly selected for resistant viruses, the isolates obtained varied in their overall level of resistance, in their cross-resistance to other non-nucleoside reverse transcriptase inhibitors (NNRTIs) and in the amino acid changes present in the reverse transcriptase (RT). The mutation Y181C was most commonly observed, often with a second mutation, such as K101E or V-106A. The amino acid change L100I was also observed upon selection. In order to determine the reproducibility of the in-vitro resistance selection process, 10 isolates resistant to UC84 were independently selected in parallel cultures. Mutations detected in the RT of these isolates were varied but included the commonly reported Y181C and V106A amino acid changes, as well as unique changes K101I, K101N, K103Q, G190A, T139I and A98S. These results demonstrate that from the heterogeneous wild-type population, antiviral agents, such as the UC compounds, may select a wide variety of virus isolates with resistance-engendering amino acid changes in the RT. In addition, the results also suggest that antiviral agents may select for resistant viruses at different rates and to different extents, offering the possibility that compounds might be identified which do not readily result in high level drug resistance.