In the vast majority of individuals, exposure of the immune system to multiple HIV-antigens during infection with HIV stimulates the development of humoral and cellular immune responses that ultimately fail to control the infection or the diseases. This failure results, at least in part, from the fact that the immunodominant epitopes are hypervariable, T cell responses are directed to a limited number of epitopes, and antibody responses against conserved, conformational epitopes are of low titer and develop late in the disease. Although immune responses that ultimately will prove successful in protecting against this disease may differ in part from those required to control the disease, the problems of hypervariable immunodominant epitopes, escape mutants, a narrow spectrum of epitopes recognized by cytotoxic T cells and lack of antibodies against conformational epitopes also complicate the design of preventive vaccines. Multiple Chain Peptides (MCPs) consist of 8 or 4 copies of the same 14 to 21 amino acid sequence containing selected, conserved epitopes. They differ from conventional peptides in that they are highly immunogenic without coupling to carrier proteins and are immunogenic in multiple MHC types. We have demonstrated that by immunizing with MCPs one can induce antibodies against conserved, conformational epitopes that are not induced by immunizing with gp120 or with the homologous monomeric peptides. These antibodies against the otherwise cryptic 419-439 conformational epitope are able to inhibit gp120-CD4 binding, to recognize oligomeric gp120 on budding virus and to neutralize low levels of primary isolates. This 419-439 also induces CD8 CTL in several strains of mice different MHC, and also T cells producing TH-1 cytokines. The proposed studies will analyze the types of immune responses induced by additional MCPs containing conserved, cryptic epitopes of gp120- in order to expand the range of epitopes against which both B and T cell immune responses can be induced. These experiments also will correlate the structure of the MCP immunogens with the types of immune responses induced, to obtain information on the relationship between structure of a peptide epitope and immunogenicity. By immunizing with a cocktail of multiple MCPs against selected conserved conformational or conserved contiguous epitopes one can avoid the dominant immune responses against hypervariable T and B epitopes that are stimulated by infection or by whole protein, and broaden immune responses against a large number of conserved epitopes. Using recently developed polyoxime chemistry, pure, homogeneous MCPs can by synthesized.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS and Related Research Study Section 1 (ARRA)
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Warren, Jon T
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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