P.I.'s abstract). A major goal of HIV research is the development of new antiviral agents that target distinct stages of the viral replicative cycle. Recently, fusion of HIV-1 with host cell membranes has been shown to require certain human """"""""co-receptor"""""""" molecules that belong to the chemokine receptor family of seven transmembrane-spanning (7-TM), G protein-coupled receptors. These molecules provide excellent targets for the majority of currently licensed pharmaceuticals. The overall goal of this project is to determine whether anti-co-receptor monoclonal antibodies (mAbs), used alone or in combination with other antiviral agents, can effectively inhibit HIV-1 replication in vitro and protect against infection in vivo using the best systems available. In the Phase I project, mAbs to the CCR5 co-receptor were generated that potently inhibit HIV-1 entry without affecting normal CCR5 activity. In the Phase II project, HIV-1 inhibitor mAbs will be generated to additional chemokine receptor molecules known to support the entry of a wide range of viral isolates. The mAbs will be extensively evaluated for biologic properties and their breadth, potency and mechanism of antiviral activity. The potential for HIV-1 to develop resistance by altering its patterns of co-receptor usage will be explored in an extensive series of in vitro studies. Specific combinations of anti-co-receptor mAbs and other antiviral agents will be examined for possible synergistic activity in preventing HIV-1 infection and the development of drug resistant mutants. MAbs and combinations that provide the most broad, potent, and sustained inhibition of HIV-1 in vitro will evaluated in vivo in the hu-PBL-SCID and SHIV-macaque models of HIV-1 infection. Here specific regimens will be tested for the ability to protect animals against infection by viruses derived from diverse HIV-1 isolates. If successful, this project would guide our selection of mAbs to be humanized and advanced into clinical development as novel agents for the treatment and prophylaxis of HIV-1 infection.
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