The goal of the proposed research is to develop novel synthetic immunogens to elicit broadly neutralizing antibody responses against HIV-1. Recent studies on the mechanism of viral membrane fusion, as well as the epitope mapping of three broadly neutralizing anti-gp41 antibodies 2F5, 4E10, and Z13 suggest that the C terminal ectodomain region of the envelope glycoprotein gp41 is a promising target for vaccine design. However, attempts to elicit 2F5-1ike neutralizing antibodies using the linear 2F5 epitope expressed in various contexts, including conformation-constrained analogs, have failed. The results suggest that the true epitopes may be more complex in nature than a simple, monomeric peptide chain. Based on the fact that the functional unit of gp41 in membrane fusion and viral entry is an oligomeric (most likely a trimeric), parallel stranded, coiled coil complex rather than a monomeric gp41, we speculate that the true epitopes for these broadly neutralizing antibodies may involve a dynamic, multivalent structure consisting of two or more strands of the C-peptide region in the gp41 complex. Our central hypothesis is that novel multivalent gp41 peptides that capture or mimic the putative multivalent format of epitopes will elicit broadly neutralizing antibodies against HIV-1. To test the hypothesis, we have synthesized a novel tetravalent gp41 peptide that contains four strands of peptide DP178 (T20) on a sugar scaffold (designated as MVP-1). Our preliminary studies have shown that the multivalent assembling has an impact on peptide conformation, and that MVP-1 is able to elicit significant neutralizing antibodies against some HIV strains in mice. This proposal is to confirm and to duplicate the neutralizing activities observed in mice through immunizing guinea pigs. Additional multivalent gp41 peptides that vary in peptide valency and sequence will be prepared and tested. The structure-immunogenicity relationships will be evaluated. It is expected that the proposed studies will yield important new data with significant relevance to the development of an effective HIV-1 vaccine.
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