Simultaneous mutations at Tyr‐181 and Tyr‐188 in HIV‐1 reverse transcriptase prevents inhibition of RNA‐dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U‐90152s

Effects of the G190A substitution of HIV reverse transcriptase on phenotypic susceptibility of patient isolates to delavirdine

“…Therefore, HIV-2 might mimic the behavior of HIV-1 RT with the substitutions Y188L and G190A. Supporting this hypothesis is the finding that introducing a Y188L substitution into HIV-2 RT in vitro resulted in sensitivity of HIV-2 RT to delavirdine and efavirenz (Bacolla et al, 1993;Fan et al, 1995b;Isaka et al, 2001;Shih et al, 1991). Structural studies of HIV-1 RT complexed with inhibitors reveal that nevirapine and BHAPs bind to the same site and interact with an overlapping but not identical set of residues in the binding pocket .…”

“…Some of these, P236L and G190E have been reported to result in reduced viral fitness (Dykes et al, 2001;Fan et al, 1995a;Kleim et al, 1994). Among these, P236L was reported to result in hypersusceptibility to non-BHAP NNRTIs (Dueweke et al, 1993;Fan et al, 1995b;Gerondelis et al, 1999;Olmsted et al, 1996). Conversely, P225H has been reported to arise in vitro following exposure to quinoxaline S-2720, and results in hypersusceptibility to delavirdine, but not to dipiridodiazepinone NNRTIs (Pelemans et al, 1997(Pelemans et al, , 1998.…”