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MIMOTOPE CONVERSION OF HIV1 CARBOHYDRATE ANTIGENS

HIV1 碳水化合物抗原的多表位转化

基本信息

批准号：
2887913
负责人：
THOMAS KIEBER-EMMONS
金额：
$ 23.85万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-30 至 2000-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2887913
关键词：
AIDS vaccines HIV envelope protein X ray crystallography carbohydrate structure concanavalin A glycosylation human immunodeficiency virus 1 immune tolerance /unresponsiveness immunoglobulin G immunoglobulin M laboratory mouse lymphocyte proliferation neutralizing antibody protein structure synthetic vaccines vaccine development

项目摘要

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.

描述（改编自申请人的摘要）：这些研究是目的是开发碳水化合物抗原相关的肽模拟表位，与HIV（1型）（HIV-1）的包膜蛋白。的理由这种方法是观察到糖基化的变化 HIV-1分离株的特征影响抗体的中和能力否则会中和原始分离物这些变化不会影响通过抗碳水化合物抗体或凝集素中和。碳水化合然而，它们是T细胞非依赖性抗原，因此存在局限性，与其免疫原性有关。为了克服这些局限性，该项目涉及碳水化合物表位的相互转换与艾滋病毒相关的肽疫苗策略，以引发T 细胞依赖性全身免疫反应。申请人假设，多肽可以模拟糖类抗原，诱导HIV特异性免疫，应答研究人员的长期目标是开发肽模拟物免疫原作为HIV-1相关碳水化合物的替代物，诱导针对HIV-1特异性免疫。在最初发表的研究中，本申请人已经表明某些模拟碳水化合物的肽可以诱导抗血清阻断HIV-1实验室无细胞感染分离株调查人员的短期目标是进一步证实肽模拟物可以诱导中和免疫应答，实验室和主要分离株，并阐明结构原理，可以被用来培养模仿设计。申请人已经已经确定含有芳香残基的特定肽基序可以有效模拟HIV-1上甘露糖基、乳糖系列和唾液酸基部分。为有效肽疫苗设计分子和结构洞察力这种模仿需要被理解。申请人正在评估通过评价动力学和结合的肽模拟表位的抗原模拟与HIV相关碳水化合物竞争的肽的参数，伴刀豆球蛋白A（Con A）和抗碳水化合物抗体分析. 拓扑相似性也正在评估使用分子 Con A-肽和抗体-肽的模拟和晶体学分析配合物免疫模拟通过小鼠免疫来评价，对比不同的肽介绍和配方，实验室和主要分离株的中和特性。