Analysis of HIV-1 core assembly and inhibition

DESCRIPTION (provided by applicant): The AIDS epidemic has claimed millions of lives, and millions more are currently infected with HIV. HAART (highly active antiretroviral therapy), which is directed against the viral reverse transcriptase (RT) and protease (PR) enzymes, is the preferred present treatment for HIV infections, and has extended the lives of many infected individuals. However, because of the capacity of HIV to acquire drug-resistance, the continued development of alternative therapies is imperative. The critical process of forming a mature virus core represents an attractive new target for antiviral therapies. Mature HIV-1 cores are conical or cylindrical structures composed of the viral capsid (CA) protein that surrounds the ribonucleoprotein complexes in virions. The morphogenesis of an infectious virus core appears to be exquisitely sensitive, and failure to form such a core is fatal to virus replication. However the mechanisms that regulate the many steps of core assembly nucleation and growth require characterization in order to understand how potential inhibitors work, and to identify how new inhibitors might block specific bottlenecks in the process. The investigations we propose address this need, and take advantage of our lab's expertise, our unique resources, and the novel approaches that we have devised and invented. Through these efforts the specific steps of HIV-1 core formation will be elucidated, and mechanisms by which these steps can be blocked will be discovered. Our aims are as follows: 1. Characterization of the mechanism of HIV-1 core assembly nucleation and its inhibition. 2. Elucidation of mature HIV core oligomerization and morphogenesis assembly steps. 3. Analysis of factors controlling mature HIV-1 core stabilities. Our investigations on the nucleation, growth and stability of HIV-1 cores will foster the development of antiviral therapeutics against new viral processes. PUBLIC HEALTH RELEVANCE: Narrative our investigations focus on the mechanism of mature HIV-1 virus core assembly and morphogenesis. We propose to characterize the steps by which HIV-1 cores are formed, to clarify how potential inhibitors of the process work, and to identify how new inhibitors might block specific bottlenecks in the process. These studies are of direct public health relevance in that they will lead to the development of new antivirals and an understanding of how they work.