Despite significant efforts, an HIV vaccine that induces protective immunity has not yet been developed. As such, much effort has been devoted to discovering and developing antiviral inhibitors of retroviral replication in hopes of preventing or delaying immunological and neurological diseases. Several chemotherapeutic drugs which include the RT and PR inhibitors are currently in clinical use. Because variant viruses have emerged that are resistant to these drugs, there is a strong incentive to search for novel anti-viral therapeutics that block additional stages of the virus life cycle. Clearly, firm comprehension of the molecular mechanisms underlying each step of the replication cycle is an essential and compelling basis for discovering and developing new antiviral therapeutics. One key target for therapeutic intervention is virus assembly. Retrovirus capsid assembly is directed by the gag gene product. Expression of the Gag protein in the absence of the other viral proteins is sufficient for the assembly of virus-like particles. Thus, this protein contains all of the necessary information for protein transport from the sites of synthesis to the sites of assembly, capsid themselves, and establish intermolecular contracts with other Gag proteins, viral RNAs and with cellular and their roles during assembly. However, very little is known about cellular contributions to virus assembly. The experiments proposed here will initially focus on identifying and characterizing cellular proteins that are required for retrovirus assembly using a simian retrovirus This virus will be initially used for determining the roles two newly identified cellular proteins play during virus morphogenesis because capsid assembly, cytoplasmic protein transport, and membrane binding and budding are genetically, biochemically, spatially, and temporally separate events for this virus. We will then build upon the knowledge gained form these studies to ask specific questions about the involvement of host cell proteins during HIV assembly. We will to focus on HIV assembly in human macrophage because it is apparent that HIV assembly in macrophage is different from that in T-cells and that macrophage play key roles during establishment of HIV infection and in immunological and in immunological and in neurological disease.
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