Epitope optimization for heterologous prime-boost HIV vaccines

异源初免-加强 HIV 疫苗的表位优化

基本信息

批准号：
9138212
负责人：
TIMOTHY J CARDOZO
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9138212
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Affect Antibodies Antibody Formation Antigens B-Lymphocyte Epitopes Binding CD8B1 gene Characteristics Codon Nucleotides Communities Complex DNA DNA Sequence Epitopes Foundations Genetic Glycoproteins Goals HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine Human Immune response Immunization Individual Link Molecular Molecular Conformation Monoclonal Antibodies Neutralization Tests Oryctolagus cuniculus Outcome Physiological Plasma Proteins Protocols documentation Quantitative Structure-Activity Relationship Reagent Research Research Project Grants Serum Source Structure-Activity Relationship Surface System Technology Testing United States National Institutes of Health Ursidae Family V3 Loop Vaccine Clinical Trial Vaccine Design Vaccines base design env Genes high reward high risk human subject immunogenic improved innovation interest novel polyclonal antibody programs public health relevance research study resistant strain response three dimensional structure vaccine trial vector

项目摘要

DESCRIPTION (provided by applicant): As a result of the RV144 trial and numerous recent studies, heterologous prime-boost HIV vaccine strategies have emerged as the leading approach to elicit immune responses that could protect against HIV infection. The molecular basis of the heterologous approach over homologous approaches is not well understood, however. In particular, immune responses to vector or DNA priming immunizations that are then amplified by protein boost immunization are complex and obscure. In this proposal, we will perform experiments that may clarify unsuspected, fundamental aspects of the immune responses to the prime that are amplified by the protein boost. To test this, we will control for many factors in a heterologous prime-boost experiment, varying only the conformational B-cell epitopes between prime and boost. Our innovative hypothesis is that the conformation of B-cell epitopes in the prime influences those self-same epitopes in the boost. Rabbits will be immunized with an array of DNA primes constructed to express or exclude specific immunogenic HIV variable loop epitopes and then boosted with an immunofocused protein immunogen that exclusively bears those epitopes. We expect to observe whether the expression of a conformational epitope in the prime amplifies or retards elicitation of neutralizin antibodies from that self-same epitope provided on the protein boost. The results will clearly provide the first consistent rationale for selecting or designing HIV env genes for use in priming immunizations. This exploratory R21 project will thus form the foundation for a unique long-term research program into the molecular details of the interaction between priming and boosting immunizations in a heterologous prime-boost strategy. These details may be crucial for designing an efficacious HIV vaccine.

描述（由适用提供）：由于RV144试验和许多最近的研究，异源促进艾滋病毒疫苗策略已成为引起可以预防HIV感染的免疫反应的主要方法。然而，异源方法的分子基础在同源方法上尚不清楚。特别是，对载体或DNA启动免疫免疫的免疫回应，然后通过蛋白质增强的免疫抑制进行扩增，是复杂而晦涩的。在此提案中，我们将进行实验，这些实验可能会阐明免疫回报的未提交的基本方面，这些方面已被蛋白质增强所扩增。为了测试这一点，我们将在异源的促进实验中控制许多因素，仅在素数和增强之间改变了B-cell表位。我们的创新假设是，B元中B细胞表位的构象影响了增强中这些自称表位。兔子将用构建的一系列DNA素数对兔子进行免疫，以表达或排除特定的免疫原性艾滋病毒可变循环表位，然后用专门带有这些表位的免疫限制蛋白免疫原促进。我们期望观察到构象表位在质子放大器中的表达或降低了中性蛋白抗体从蛋白质增强上提供的自相表位的启发。结果清楚将提供第一个一致的理由，用于选择或设计用于启动免疫抑制的HIV ENV基因。因此，该探索性R21项目将奠定一个独特的长期研究计划的基础，以在异源促进策略中启动和增强免疫抑制之间的相互作用的分子细节。这些细节对于设计有效的HIV疫苗可能至关重要。