Testing of VIF Inhibitors Against Clinical Isolates and Animal Study Support

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Core B will support the overall grant application by providing specific in vitro and in vivo tests of promising Vif inhibitor candidates. The first aim is to test the efficacy and toxicity of promising Vif inhibitor candidates in human PBMC-based assays using clinical HIV-1 isolates including neurotropic isolates. The second aim is to test promising Vif inhibitor candidates in the HIV-1 Hollow Fiber Mouse model. Hollow fibers filled with HIV-1 infected cells will be implanted subcutaneously and intraperitoneally into Balb/c mice. Subsequently, the mice will be treated intraperitoneally with the Vif inhibitor candidates. The mice will be monitored for acute toxicity and the fibers evaluated for efficacy against HIV-1 replication. The third aim is to perform quantitative RNA viral load determinations on rhesus macaque plasma and viral load samples in support of the SIV/primate studies at New England Primate Research Center (Project 3). For the quantitative viral load measurements, TAQMAN RT-PCR using an ABI7900 sequencer will be performed. Primers, probe, and standard are from the gag region of SIV. The relevance of this project to public health: Currently, about 1 million people are infected with HIV in the United States. In addition, 40,000 new infections are occurring each year. So far, about 500,000 persons died from complications of HIV-infection in the US. In the last 15 years, a variety of anti-HIV compounds have been developed but these compounds only control but do not cure the infection. All of the compounds currently licensed are directed against two HIV enzymes or against virus/cell fusion. Recently, the interaction of another HIV protein, Vif, with a cellular protein (APOBEC3G) was discovered. The newly identified compounds that inhibit this interaction have the potential to cure the infection with HIV-1 since Vif is required for replication in primary human cells.