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. In contrast to rhesus macaques, pigtail macaques express low levels of DC-SIGN in myeloid-lineage DCs, providing a potential in vivo model to study the DC-SIGN contribution to viral pathogenesis. 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 resistant mutants when grown in the presence of NNRTIs. RT-SHIVmne replicates less well than the parental SIVmne in cultured cells. This replication defect correlates with a reduced amount of RT in RT-SHIVmne particles. RT-SHIVmne replication has been tested in pigtail macaques. High viral loads have been detected over six months in six infected animals. We plan to assay the effect of single-dose NNRTI therapy and repeated-dose single-drug and combination therapy on the suppression of RT-SHIVmne replication and the development of antiviral resistance. We also plan to explore whether the RT-SHIVmne/pigtail model is suitable for mucosal transmission questions as well as studying the destruction of gut-associated lymphatic tissue. We are evaluating this in vivo model for NNRTI studies in close consultation with anti-RT resistance experts present within the HIV Drug Resistance Program (DRP), the DRP Virology Core (headed by Dr. Sarah Palmer), the SAIC AIDS Vaccine Program, and extramural collaborators possessing extensive experience in the characterization of SIVmne pathogenesis in the pigtail macaque model.
| Ambrose, Zandrea; KewalRamani, Vineet N; Bieniasz, Paul D et al. (2007) HIV/AIDS: in search of an animal model. Trends Biotechnol 25:333-7 |
| Ambrose, Zandrea; Palmer, Sarah; Boltz, Valerie F et al. (2007) Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy. J Virol 81:12145-55 |
| Ambrose, Zandrea; Boltz, Valerie; Palmer, Sarah et al. (2004) In vitro characterization of a simian immunodeficiency virus-human immunodeficiency virus (HIV) chimera expressing HIV type 1 reverse transcriptase to study antiviral resistance in pigtail macaques. J Virol 78:13553-61 |
