ENHANCED IMMUNOGENICITY OF GLYCOSYL DEFICIENT SIV ENV

糖基缺陷型 SIV ENV 的免疫原性增强

• 批准号: 2751242
• 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 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2751242
• 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 对抗人类免疫缺陷病毒（1 型）（HIV-1）。 然而，方法 迄今为止未能开发出诱导中和抗体的疫苗 针对 HIV-1 初级分离株的反应。 此故障似乎会导致 从病毒包膜的两个特点来看：抗原性低、抗原性差 免疫原性。 如何最大化成熟包膜上表位的表达 因此，增强免疫原性是理性研究的关键问题。 疫苗设计。 在最近的研究中，感染了缺乏 SIV 突变株的恒河猴 gp120 V1 可变区及其周围的特定糖基化位点 发现产生的抗体反应不仅可以有效中和 突变型 SIV 毒株，也包括完全糖基化的野生型病毒。 这 表明可以有效引发中和抗体 针对原代慢病毒的反应。 它进一步表明 糖基缺陷突变体具有增强的免疫原性并且是潜在的 候选疫苗。 该项目的主要目标是了解 糖基缺陷型 SIV 免疫原性增强的分子基础 通过定义和表征包含包膜的抗体 中和反应。 申请人提议研究由以下引起的抗体反应： 通过分离和在分子水平上形成糖基缺陷的包膜 表征从噬菌体展示文库制备的重组抗体 来自这些猴子。 研究人员将表征结合 单克隆抗体 (mAb) 和抗野生型和 糖基缺陷的 SIV 包膜详细信息。 进一步剖析响应 并表征重要的抗体的特异性 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 碳水化合物增加了有效中和 B 细胞表位的暴露， 使表位更具免疫原性。 然而，还有其他解释，例如 碳水化合物密度对一般免疫原性的影响无法确定 打折的。 拟议的研究应允许增强的起源 待测试糖基缺陷的 SIV 包膜的免疫原性。 了解 SIV 模型中增强的免疫原性将为我们奠定基础 以知识为基础开发更具免疫原性的候选疫苗 HIV-1。