Testing antiretroviral drug efficacy in conventional mice infected with chimeric HIV-1

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Abstract
Objective: We previously described chimeric HIV-1, EcoHIV, which can infect mouse cells in culture and cause spreading infection in conventional immunocompetant mice. We have now applied this system as a model for preclinical evaluation of anti-retroviral drugs. Design and methods: We used chimeric virus EcoHIV/NDK constructed on the backbone of subtype D NDK. EcoHIV/NDK expression in mice was characterized 5–10 days after infection by testing viral DNA, RNA, and protein burdens in spleen and macrophages by real-time PCR (QPCR), RT–PCR, and p24 ELISA. For antiviral evaluation, groups of 5–7 mice were pretreated with 2′,3′–dideoxycytidine (ddC), abacavir, or vehicle; mice were then infected with EcoHIV/NDK, treatment maintained for additional 48 h, and tested for viral DNA and RNA burdens in spleens and macrophages by QPCR. Results: EcoHIV/NDK infected mice reproducibly showed viral burdens of up to 1.4 × 104 viral DNA copies and 200 pg p24 per 106 spleen cells and expressed spliced Vif RNA and mature p24 in macrophages 5–10 days after infection. Treatment of mice with 60 or 300 mg ddC/kg/day blocked EcoHIV/NDK infection in a dose-dependent manner with significantly lower viral DNA and RNA burdens at both drug doses (P < 0.001) in the spleens of infected mice. Abacavir tested at 100 mg/kg/day caused 96% inhibition of viral DNA synthesis in spleen and it almost completely abolished viral spliced RNA synthesis in spleens and macrophages. Conclusions: The system of chimeric HIV-1 infection of mice permits rapid, statistically powerful, and inexpensive evaluation of antiretroviral drugs in vivo.