The V3 loop of gp120 is a major neutralizing determinant of HIV-1. Segments of V3 or its immediate vicinity form the binding site for the gp120 co-receptors on T-cells and macrophages and its sequence determines the phenotype of the virus. Antibody binding to V3 or deletion of V3 prevent virus fusion with the target cells, and thus abolishes infectivity. Neutralization of a variety of HIV-1 strains, including field isolates, have shown that serum obtained after immunization with antigens containing V3 peptides of different strains. Immunization with a """"""""cocktail"""""""" of peptides may overcome the variability problem. Phase I clinical trials of candidate vaccines containing V3 peptides have been conducted in the US and in France. The principal aim of the research proposed here is to solve the three-dimensional structure of the 0.5b Fv complex with a V3 peptide, RP 135, using multi-dimensional NMR. These studies will provide the first structural information about V3 and will identify the residues that are important for binding to neutralizing antibodies and the residues that determine the conformation of V3. The structue of V3 will deomnatrate which residues can potentially interact with the co-receptor for gp120 on T-cells and macrophages and why certain positions are variable while others are more conserved. The structural information obtained in these studies should be helpful in designing optimal peptide immunogens to be used in a peptide based vaccine against HIV.
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