NOVEL ASSAY FOR MEASURING THE INHIBITION OF HIV-1 ENTRY

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Antiretroviral therapy has provided tremendous clinical benefit to HIV/AIDS patients. However, treatment failure is common and due mostly to emergence of resistant viruses. Commercial susceptibility assays for HIV-1 reverse transcriptase and protease inhibitors are playing an increasingly important role in the routine management of HIV-1 infected patients. Drugs that target different aspects of HIV-1 replication, primarily virus entry, are urgently needed as well. Practical assays to support the development of entry inhibitors and detect resistant viruses in patients are not available. A prophylaxis vaccine would be a powerful weapon against the AIDS pandemic. Today's most promising candidates are designed to elicit neutralizing antibodies that block virus entry. Evaluation of vaccine candidates requires large clinical trials. Consequently, high-throughput assays for measuring virus neutralization activity are urgently needed. In phase I we will demonstrate feasibility of a novel assay that measures inhibition of viral attachment and entry. We will construct a vector to express HIV-1 envelope proteins and a retroviral vector that contains a reporter gene for measuring viral replication. Envelope trans-complemented viruses will be used to infect cell lines that express HIV-1 receptors. This assay will become a valuable tool for characterizing drug candidates, optimizing patient treatment, and supporting vaccine development. PROPOSED COMMERCIAL APPLICATION: We intend to develop a rapid, sensitive, phenotypic assay to measure the susceptibility of HIV-1 to a wide variety of virus entry inhibitors. This assay will supplement existing commercial assays that measure susceptibility to reverse transcriptase and protease inhibitors. The assay will be marketed to physicians to assist in HIV/AIDS patient care, as well as pharmaceutical companies to support their drug and vaccine development programs.