MIMOTOPE CONVERSION OF HIV1 CARBOHYDRATE ANTIGENS

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DESCRIPTION (adapted from the applicant's abstract): These studies are aimed at developing peptide mimotopes of carbohydrate antigens associated with the envelope proteins of the HIV (Type 1)(HIV-1). The rationale for such an approach is the observation that changes in the glycosylation profiles of HIV-1 isolates affect the neutralization ability of antibodies that otherwise neutralize primary isolates. Such changes do not affect neutralization by anti-carbohydrate antibodies or lectins. Carbohydrates are T cell-independent antigens however, and as such, there are limitations associated with their immunogenicity. To overcome these limitations, this project is concerned with the interconversion of carbohydrate epitopes associated with HIV into a peptide-based vaccine strategy to elicit a T cell-dependent systemic immune response. The applicants hypothesize that peptides can mimic carbohydrate antigens, inducing HIV specific immune responses. The investigators' long-time goal is to develop peptide mimic immunogens as surrogates for HIV-1 associated carbohydrates for the induction of specific immunity against HIV-1. In initial published studies, the applicants have shown that certain peptides that mimic carbohydrates can elicit antisera which can block cell free infection of HIV-1 laboratory isolates. The investigators' short-term goal is to further substantiate that peptide mimetics can induce neutralizing immune responses to both laboratory and primary isolates and to elucidate structural principles that can be manipulated to foster mimetic design. The applicants have established that particular peptide motifs containing aromatic residues can effectively mimic mannosyl, lacto-series and sialyl moieties on HIV-1. For effective peptide vaccine design both molecular and structural insight of such mimicry needs to be understood. The applicants are evaluating the antigenic mimicry of peptide mimotopes by evaluating kinetic and binding parameters of peptides that compete with HIV-associated carbohydrates for concanavalin A (Con A) and an anti-carbohydrate antibody using BIACORE analysis. Topological similarities are also being evaluated using molecular modeling and crystallographic analysis of Con A-peptide and antibody-peptide complexes. Immunological mimicry is evaluated by immunization of mice, contrasting different peptide presentations and formulations and evaluating neutralization properties for both laboratory and primary isolates.