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Topology, Antigenicity, and Immunogenicity of the C-terminal Tail (CTT) of HIV-1

HIV-1 C 末端尾 (CTT) 的拓扑结构、抗原性和免疫原性

基本信息

批准号：
8638885
负责人：
Ronald C Montelaro
金额：
$ 51.51万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8638885
关键词：
AIDS vaccine development Address Adenovirus Vector Affect Antibodies Antibody Formation Antigens Attenuated Biochemical Biological Assay C-terminal Cells Cellular Membrane Charge Chemicals Chimera organism Chimeric Proteins Codon Nucleotides Complex Conserved Sequence Drug Targeting Engineering Environment Experimental Models Gagging Goals HIV HIV Envelope Protein gp120 HIV Envelope Protein gp41 HIV-1 Immune Sera Immune Targeting Immunization Immunologics Immunology Infection Influenza Hemagglutinin Length Lipid Bilayers Maps Mediating Membrane Membrane Fusion Membrane Lipids Membrane Proteins Minor Modeling Molecular Conformation Mutation Oryctolagus cuniculus Pathogenesis Phenotype Point Mutation Procedures Process Production Property Proteins Relative (related person)Resolution Role SIV Series Signal Transduction Solid Specificity Structure Surface Tail Techniques Testing Time Vaccines Variant Viral Virion Virus Virus-like particle base design env Gene Products immunogenic immunogenicity influenzavirus insight neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel particle polyclonal antibody public health relevance response vector vaccine

项目摘要

DESCRIPTION (provided by applicant): The HIV-1 envelope proteins are recognized as primary immune targets during infection and have been a major focus of AIDS vaccine development to elicit enduring broadly neutralizing antibody responses. These efforts have largely focused on the gp120 and gp41 ectodomains, based on the assumption that the gp41 C-terminal tail (CTT) was not exposed and important for envelope immunogenicity. Recent studies from our lab and others, however, clearly indicate that the CTT is a major determinant of HIV-1 envelope structure, function, and antigenicity and that the CTT can be a potent target for neutralizing antibodies directed to relatively conserved protein segments. Based on these observations, we hypothesize that the topology of the HIV gp41 CTT relative to the lipid bilayer is dynamic, and that CTT sequences are, at least transiently, located on the exterior of the viral or cellular lipid bilayer. We postulate further that CTT sequences are important determinants of Env antigenic and immunogenic properties, both by their association with other Env domains and as distinct immunologic targets, including neutralizing antibodies directed to conserved CTT sequences. We propose in this application to test this hypothesis in two specific aims: (i), to produce a definitive topological map of the CTT sequences relative to viral or cellular membranes and the influence of Gag association or fusion process on this topology, and (ii) to assess the role of the CTT as a determinant of Env immunogenicity and antigenicity, especially as related to neutralizing antibodies. The structural studies will utilize high-resolution membrane protein topology mapping techniques and antibody reactivity assays to define CTT structure in the context of virus- and cell-associated Env and in the context of novel chimeric proteins containing the HIV-1 CTT fused to the ectodomain of influenza virus HA envelope protein. The immunologic studies will employ experimental immunization of rabbits using established adenovirus vector or VLP vaccine procedures with codon optimized HIV-1 full length of truncated Envs or the engineered HA-CTT constructs to isolate CTT immunogenicity in the context of viral or cellular membranes. It is anticipated that the results of these studies will for the first time define the topology of the HIV-1 CTT and characterize its role as an immunogenic determinant and its potential as an immunogen to elicit broadly neutralizing antibodies to conserved sequences.

描述（由申请人提供）：HIV-1 包膜蛋白被认为是感染期间的主要免疫靶标，并且一直是艾滋病疫苗开发的主要焦点，以引发持久的广泛中和抗体反应。这些工作主要集中在 gp120 和 gp41 胞外域上，假设 gp41 C 末端尾部 (CTT) 未暴露且对包膜免疫原性很重要。然而，我们实验室和其他实验室最近的研究清楚地表明，CTT 是 HIV-1 包膜结构、功能和抗原性的主要决定因素，并且 CTT 可以成为中和针对相对保守的蛋白质片段的抗体的有效靶标。基于这些观察，我们假设 HIV gp41 CTT 相对于脂质双层的拓扑是动态的，并且 CTT 序列至少暂时位于病毒或细胞脂质双层的外部。我们进一步假设，CTT 序列是 Env 抗原和免疫原性特性的重要决定因素，因为它们与其他 Env 结构域相关，并且作为不同的免疫靶标，包括针对保守 CTT 序列的中和抗体。我们建议在本申请中测试这一假设的两个具体目标：（i），生成相对于病毒或细胞膜的CTT序列的明确拓扑图，以及Gag关联或融合过程对该拓扑的影响，以及（ii）评估CTT作为Env免疫原性和抗原性决定因素的作用，尤其是与中和抗体相关的作用。结构研究将利用高分辨率膜蛋白拓扑图谱技术和抗体反应性测定来定义病毒和细胞相关 Env 背景下的 CTT 结构，以及包含与流感病毒 HA 包膜蛋白胞外域融合的 HIV-1 CTT 的新型嵌合蛋白。免疫学研究将采用已建立的腺病毒载体或 VLP 疫苗程序对兔子进行实验性免疫，并使用密码子优化的 HIV-1 全长截短 Env 或工程化的 HA-CTT 构建体来分离病毒或细胞膜背景下的 CTT 免疫原性。预计这些研究的结果将首次定义 HIV-1 CTT 的拓扑结构，并表征其作为免疫原性决定因素的作用及其作为免疫原引发针对保守序列的广泛中和抗体的潜力。