ENHANCED IMMUNOGENICITY OF GLYCOSYL DEFICIENT SIV ENV

描述(改编自申请人的摘要)：中和 抗体可能是研制有效疫苗的关键。 抗人类免疫缺陷病毒(1型)(HIV-1)。然而，方法 到目前为止，还没有开发出诱导中和抗体的疫苗 对HIV-1初级分离株的反应。这一失败似乎导致 来自病毒包膜的两个特点：抗原性低和差 免疫原性。如何在成熟的包膜上最大限度地表达表位 因此，提高免疫原性是理性的关键问题 疫苗设计。 在最近的研究中，感染SIV突变株的恒河猴缺乏 Gp120 V1可变区及其周围的特定糖基化位点是 发现能产生抗体反应，不仅能有效中和 变异的SIV毒株也是完全糖基化的野生型病毒。这 提示有可能有效地诱导中和抗体。 对主要慢病毒的反应。它进一步表明， 糖基缺陷突变株具有增强免疫原性的潜力 候选疫苗。本项目的主要目标是了解 糖基缺陷SIV免疫原性增强的分子基础 通过定义和表征包括 中和反应。 申请者建议研究由病毒引起的抗体反应 通过分离和分离在分子水平上缺乏糖基的包膜 噬菌体展示文库中重组抗体的鉴定 从这些猴子身上。调查人员将描述 抗野生型和抗野生型的单抗和抗血清 缺乏糖基的SIV包膜的详细信息。为了进一步剖析人们的反应 并表征抗体的特异性，这些抗体对 保护，申请者将进行被动转移和病毒挑战 实验。目前的假设是，缺乏具体的 碳水化合物增加了一个强有力的中和B细胞表位的暴露， 使表位更具免疫原性。然而，其他解释，如 碳水化合物密度对一般免疫原性的影响不能 打折。建议的研究应该允许增强的 待检测的糖基缺陷SIV包膜的免疫原性。 了解SIV模型中增强的免疫原性，将为 以知识为基础开发更具免疫原性的候选疫苗 HIV-1。

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.