Optimizing protective vaccine targets in the V1/V2 domain of HIV-1 gp120

优化 HIV-1 gp120 V1/V2 结构域中的保护性疫苗靶标

基本信息

批准号：
8501371
负责人：
ABRAHAM PINTER
金额：
$ 51.55万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8501371
关键词：
Affinity Animals Antibodies Antibody Formation Antigens Binding Cells Chimeric Proteins Cloning Consensus Sequence DNA Drug Formulations Epitopes Genes Goals HIV HIV Envelope Protein gp120 HIV vaccine HIV-1 Heterogeneity Immune Immune response Immunization Immunoprecipitation Infection Integrins Lead Learning Light Macaca Measures Memory B-Lymphocyte Methods Modeling Monoclonal Antibodies Mutation Oryctolagus cuniculus Participant Polysaccharides Positioning Attribute Property Protein Glycosylation Proteins Protocols documentation Relative (related person)Role Series Serum Site Specificity Structure T-Lymphocyte Testing Thailand Transfection Vaccinated Vaccination Vaccines Variant Viral Virus Diseases base design expression vector glycosylation immunogenicity in vivo mutant neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel programs protein folding receptor research study response scaffold screening simian human immunodeficiency virus vaccine development vector

项目摘要

DESCRIPTION (provided by applicant): Recent information has shed new light on the importance of the V1/V2 domain of HIV-1 in viral infection and as a potential target for protective vaccines. The V1/V2 domain has been shown to be a critical determinant of an increasing number of monoclonal antibodies (mAbs) isolated from HIV-infected subjects that that target quaternary neutralization epitopes and possess broad and potently neutralizing activities. In addition to the role of the V1/V2 region as a classical neutralization target other evidence has accumulated showing that the interaction between a conserved V2 sequence and the ¿4¿7-integrin receptor stimulates infection of a fraction of activated T cells in the gut that may be important for infection in vivo, and that this interaction is inhibited by anti-V2 mAbs. Finally, a analysis of immune parameters in the RV144 vaccine trial recently carried out in Thailand showed that antibodies that bind to a V1/V2 fusion protein that we developed uniquely correlated with protection. Studies from our lab and others have shown that potent V1/V2 neutralization targets are both highly conformational and glycan-dependent, and developing V1/V2-based vaccines is complicated by the structural heterogeneity of this region, due to variation in both protein folding and glycosylation. The aims of this project are to fully characterize the structural, functional and immunological properties of the V1/V2 domain, to identify and characterize protective epitopes in this region and to develop immunogens and vaccine strategies specific for conserved V1/V2 epitopes that efficiently elicit antibodies that contribute to protection against infection. The efficacy of novel V1/V2 immunogens developed by this program will be evaluated initially in a rabbit model by Dr. Shan Lu at UMass and towards the end of this study in a non-human primate challenge model by Dr. Shiu-Lok Hu at the WNPRC. The optimization of targets in the V1/V2 domain arising from these studies should be an important contribution towards the design of more effective HIV vaccines.

描述（由应用程序提供）：最新信息已为HIV-1的V1/V2域在病毒感染中的重要性提供了新的启示，并作为保护性的潜在目标疫苗。 V1/V2结构域已被证明是从靶向第四纪神经化表位和潜在中和活性的HIV感染受试者中分离出的越来越多的单克隆抗体（mAb）的关键确定。除了V1/V2区域作为经典神经化目标的作用外，其他证据都积累了表明，保守的V2序列与€4€7-整合蛋白受体之间的相互作用刺激了肠道中激活的T细胞的感染，这可能对Vivo感染很重要，并且这种相互作用抑制了这种相互作用，并且该相互作用抑制了Atti-V2 Mabs。最后，对最近在泰国进行的RV144疫苗试验中的免疫参数的分析表明，与V1/V2融合蛋白结合的抗体与我们开发的与保护与保护独特相关。来自我们实验室和其他人的研究表明，有效的V1/V2神经化靶标既高构象和聚糖依赖性，并且由于蛋白质折叠和糖基化的变化，该区域的结构异质性因该区域的结构异质性而变得复杂。该项目的目的是充分表征V1/V2结构域的结构，功能和免疫学特性，以识别和表征该地区的受保护表位，并开发针对保存的V1/V2表位的免疫原子和疫苗策略，这些策略有效地引起有助于保护感染的抗体。该程序开发的新型V1/V2免疫原子的效率最初将由UMass的Shan Lu博士在兔子模型中进行评估，并在WNPRC的Shiu-Lok Hu博士的非人类灵长类动物挑战模型中进行了这项研究的结束。这些研究引起的V1/V2结构域中靶标的优化应该是设计更有效的HIV疫苗的重要贡献。