RT-SHIV, an infectious CCR5-tropic chimeric virus suitable for evaluating HIV reverse transcriptase inhibitors in macaque models

RT-SHIV exhibited in vitro characteristics of an infectious CCR5-tropic chimeric virus. This virus was not only highly sensitive to HIV-1 RT specific NNRTIs; its replication was also inhibited by a variety of NRTIs and protease inhibitors. For in vivo vaginal transmission studies, macaques were either pretreated with a single dose of DMPA (depot medroxyprogesterone acetate) or left untreated before intravaginal inoculation with 500 or 1,000 TCID50 of RT-SHIV. All macaques became systemically infected by 2 or 3 weeks post-inoculation exhibiting persistent high viremia, marked CD4+T cell depletion, and antiviral antibody response. DMPA-pretreated macaques showed a higher mean plasma viral load after the acute infection stage, highly variable antiviral antibody response, and a higher incidence of AIDS-like disease as compared with macaques without DMPA pretreatment.This chimeric RT-SHIV has exhibited productive replication in both macaque and human PBMCs, predominantly CCR5-coreceptor usage for viral entry, and sensitivity to NNRTIs as well as other anti-HIV compounds. This study demonstrates rapid systemic infection in macaques following intravaginal exposure to RT-SHIV. This RT-SHIV/macaque model could be useful for evaluation of NNRTI-based therapies, microbicides, or other preventive strategies.Heterosexual contact is the predominant route of virus transmission for the HIV epidemics especially in the developing countries worldwide, where women are most vulnerable [1]. The pandemic spread of HIV/AIDS through sexual contact and the slow progress towards an effective vaccine have prompted the search for effective vaginal and rectal microbicides to help mitigate HIV mucosal transmission [2-10]. Various agents have been investigated as topical anti-HIV microbicides including nonnucleoside reverse transcriptase inhibitors (NNRTIs) [2,3,5,11-23]. For an effective preclinical evaluation of these agents, validated animal models are urgently needed. Ideally, the challenge vi