SENSITIVITY RESISTANCE PROFILE OF A SIMIAN IMMUNODEFICIENCY VIRUS CONTAINING THE REVERSE-TRANSCRIPTASE GENE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) TOWARD THE HIV-1-SPECIFIC NONNUCLEOSIDE REVERSE-TRANSCRIPTASE INHIBITORS

To develop an animal model for the therapy of AIDS with human immunodeficiency virus type 1 (HIV-1)specific reverse transcriptase (RT) inhibitors, we recently constructed a hybrid simian immunodeficiency virus (SIV)/HIV-1 in which the RT gene of SIV was replaced by the RT gene of HIV-1. This chimaeric virus, designated RT-SHIV, was found to be markedly sensitive to the inhibitory effects of both nucleoside (ddN) and non-nucleoside RT inhibitors (NNRTIs). In contrast, SIV was inhibited only by ddNs (i.e., 3TC and AZT), but not NNRTIs. When RT-SHN was grown in the presence of 3TC, nevirapine, TSAO-m(3)T or the thiocarboxanilide UC-42 drug-resistant mutant virus strains emerged in cell culture as rapid as for HIV-1(mg). The antiviral sensitivity/resistance spectrum of the mutant RT-SHIV strains against NNRTIs and ddNs, and the nature of the mutations that appeared in their RT were similar to those of the mutant HIV-1 strains that were selected under identical experimental conditions. Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model. (C) 1995 Academic Press, Inc.