A single amino acid change at Leu-188 in the reverse transcriptase of HIV-2 and SIV renders them sensitive to non-nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are selective for human immunodeficiency virus type 1 (HIV-1) and generally not effective on HIV-2 or simian immunodeficiency virus (SIV). Only SIVagm was found to be s ensitive to NNRTIs. When the amino acid differences in RT between SIVmac an d SIVagm were compared with the known amino acid substitutions of NNRTI-res istance variants of HIV-1, we came to consider that the amino acid residue Leu-188 of HIV-2 and SIVmac might be related to their resistance to NNRTIs. To test this hypothesis, we substituted Leu-188 to Cps or Tyr in HIV-2 and SIVmac, and examined sensitivity of the mutant molecular clones to NNRTIs. The L188Y mutant of HIV-2 became completely sensitive to delavirdine and e favirenz, while that of SIVmac was also significantly sensitive to these NN RTIs. We further isolated NNRTI-resistant variants from these mutant viruse s and determined amino acid substitutions in RT. The roles of the observed substitutions in NNRTI-resistance were further confirmed by site-directed m utagenesis. Our study reveals the crucial role of L188 in the natural resis tance of HIV-2 and SIVmac to NNRTFIs. Furthermore, the observed substitutio ns in RT of HIV-2 and SIVmac support the common mechanism of action of NNRT Is against HIV-1, HIV-2 and SIV.