We have developed an HIV-1/SIV chimeric virus (RT-SHIVmne) that is susceptible to nonnucleoside reverse transcriptase inhibitors (NNRTIs). NNRTIs are important antiviral agents used to treat HIV-1 infection in patients; however, SIVs are naturally resistant to NNRTIs. We elected to use a pathogenic isolate of SIVmne as the basis for constructing the SHIV. SIVmne infects pigtail macaque CD4+ T cells and monocytes/macrophages, cells that could be significant reservoirs for persistent virus replication. RT-SHIVmne replaces the SIV RT coding region with the RT coding region from HIV-1. Our in vitro studies indicate that RT-SHIVmne is appropriately sensitive to NNRTIs used to treat HIV-1-infected patients and generates the same resistance mutations when grown in the presence of NNRTIs. RT-SHIVmne replication has been tested in pigtail macaques. High, persistent viral loads correlate to a gradual decline in CD4+ T cells and mortality with 1-1.5 years of infection. Significantly, we have also demonstrated that an NRTI/NNRTI cocktail, commonly used to treat HIV-1 patients, is highly effective in suppressing virus replication in this model. In a majority of treated animals, RT-SHIVmne can not be detected in the blood plasma after several weeks of therapy. Nonetheless, when treatment is stopped, virus rebounds to pre-therapy levels indicating there are persistent reservoirs. We are now using this model to understand two questions that are difficult to study clinically because of ethical or sampling constraints. We are evaluating the effect of frequent treatment interruptions on the evolution of antiviral resistance. We are also seeking the tissue source of RT-SHIVmne reservoirs that persist during therapy.