ENHANCED IMMUNOGENICITY OF GLYCOSYL DEFICIENT SIV ENV

糖基缺陷型 SIV ENV 的免疫原性增强

• 批准号: 2887881
• 负责人: PAUL W PARREN
• 金额: $ 26.25万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887881
• 关键词: AIDS vaccines; HIV envelope protein; Macaca mulatta; antibody neutralization test; antibody titering; bone marrow; cross immunity; disease /disorder model; gene targeting; glycosylation; immunoglobulin G; monoclonal antibody; neutralizing antibody; passive immunization; protein structure; simian immunodeficiency virus; tissue /cell culture; vaccine development; vaccinia virus

DESCRIPTION (adapted from the applicant's abstract): Neutralizing antibodies may be critical in the development of an effective vaccine against human immunodeficiency virus (Type 1) (HIV-1). However, approaches to date have failed to develop vaccines that induce neutralizing antibody responses against primary isolates of HIV-1. This failure appears to result from two viral envelope characteristics: low antigenicity and poor immunogenicity. How to maximize expression of epitopes on mature envelope and enhance immunogenicity therefore are critical questions for rational vaccine design. In recent studies, rhesus macaques infected with mutant SIV strains lacking specific glycosylation sites in and around the gp120 V1 variable region were found to develop antibody responses that potently neutralized not only the mutant SIV strains but also fully glycosylated wild-type virus. This indicates that it is possible to effectively elicit neutralizing antibody responses against a primary lentivirus. It further suggests that glycosyl-deficient mutants have enhanced immunogenicity and are potential vaccine candidates. The major goal of this project is to understand the molecular basis of the increased immunogenicity of glycosyl-deficient SIV envelope by defining and characterizing the antibodies comprising the neutralizing response. The applicants propose to study the antibody response elicited by glycosyl-deficient envelope at the molecular level by isolating and characterizing recombinant antibodies from phage-display libraries prepared from these monkeys. The investigators will characterize the binding of monoclonal antibodies (mAbs) and antisera to wild-type and glycosyl-deficient SIV envelope in detail. To further dissect the response and to characterize the specificities of antibodies important for protection, the applicants will perform passive transfer and viral challenge experiments. The present hypothesis is that the absence of specific carbohydrate increases exposure of a potent neutralizing B cell epitope, making the epitope more immunogenic. However, other explanations such as effects due to carbohydrate density on general immunogenicity cannot be discounted. The studies proposed should allow the origin of the enhanced immunogenicity of glycosyl-deficient SIV envelope to be tested. Understanding enhanced immunogenicity in the SIV model, will set the stage for knowledge-based development of more immunogenic candidate vaccines for HIV-1.

描述（改编自申请人的摘要）：中和 抗体对于开发有效疫苗可能至关重要 针对人免疫缺陷病毒（1型）（HIV-1）。 但是，方法 迄今为止未能开发诱导中和抗体的疫苗 对HIV-1的主要分离株的反应。 这个失败似乎结果 来自两个病毒包膜特征：低抗原性和差 免疫原性。 如何在成熟的包膜上最大化表达的表达 因此，增强免疫原性是理性的关键问题 疫苗设计。 在最近的研究中，缺乏突变体SIV菌株感染的恒河猕猴 GP120 V1变量区域内及其周围的特定糖基化位点为 发现产生抗体反应，不仅在 突变的SIV菌株，但也完全糖基化的野生型病毒。 这 表明有效引起中和抗体 针对原发性慢病毒的反应。 进一步表明 缺陷糖基的突变体具有增强的免疫原性，并且潜在 候选疫苗。 该项目的主要目标是了解 糖基缺陷SIV的免疫原性增加的分子基础 通过定义和表征包括包含的抗体的信封 中和反应。 申请人建议研究由 通过分离和 表征来自准备的噬菌体抗体的重组抗体 从这些猴子那里。 调查人员将表征结合 单克隆抗体（mAb）和抗野生型抗体 详细详细介绍糖基缺陷型SIV信封。 进一步剖析响应 并表征对抗体的特异性 保护，申请人将进行被动转移和病毒挑战 实验。 目前的假设是缺乏特定的 碳水化合物增加有效中和中和B细胞表位的暴露， 使表位更加免疫原性。 但是，其他解释，例如 由于碳水化合物密度对一般免疫原性而产生的影响不可能 打折。 提出的研究应允许增强的起源 要测试的糖基缺陷型SIV包膜的免疫原性。 了解SIV模型中增强的免疫原性，将设定阶段 用于基于知识的开发更多免疫原性候选疫苗 HIV-1。