Journal
AIDS
Volume 21, Issue 8, Pages 905-909Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/QAD.0b013e3281574549
Keywords
HIV-1; chimeric HIV; HIV infection of mice; animal models of; HIV/AIDS; antiretroviral drugs; drug efficacy in vivo; anti-HIV drug testing in mice; real-time PCR; virus burden in mice; ddC; abacavir
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Funding
- NIDA NIH HHS [R01 DA017618, DA17618] Funding Source: Medline
- NINDS NIH HHS [R21 NS054580, NS54580, R01 NS043110, NS43110] Funding Source: Medline
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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 48h, 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 x 10(4) viral DNA copies and 200 pg p24 per 10(6) 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. (C) 2007 Lippincott Williams & Wilkins.
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