Isolation and characterization of simian immunodeficiency virus variants that are resistant to nonnucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) act quite specific ally on human immunodeficiency virus type 1 (HIV-1). In general, they are n ot effective on human immunodeficiency virus type 2 (HIV-2) or simian immun odeficiency virus (SIV). Only SIV strains from African green monkeys are se nsitive to several NNRTIs. Here we isolated NNRTI- and 3TC-resistant SIVagm variants. Viruses resistant to delavirdine contained V112I and M231I subst itutions, while those resistant to 3TC contained a M185I substitution. Thes e amino acids are highly conserved in HIV-1, HIV-2, SIVmac and SIVagm, and the M184I (M185I in SIVagm) substitution was observed in 3TC-resistant HIV- I and SIVmac. The roles of the observed mutations in NNRTI-resistance of SI Vagm and HIV-1 were further confirmed by site-directed mutagenesis. The pre sent results have provided a new insight into the common mechanism of sensi tivity of HIV-1 and SIVagm to NNRTIs.