Lentivirus Control by CTL and Neutralizing Antibody

通过 CTL 和中和抗体控制慢病毒

基本信息

批准号：
7348428
负责人：
ROBERT H MEALEY
金额：
$ 14.2万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7348428
关键词：
Acquired Immunodeficiency Syndrome Acute Address Alleles Antibody-mediated protection Appearance Avidity Award B-Lymphocytes Bacteriology Biological Models CD8-Positive T-Lymphocytes Capsid Proteins Cells Cessation of life Characteristics Chimeric Proteins Clinical Collaborations Communicable Diseases DNA Vaccines Defect Development Disease Epitopes Equine Infectious Anemia Virus Equus caballus Extramural Activities Faculty Funding Gagging Goals HIV-1 HIV-1 vaccine Human Immune Immunization Immunology Individual Infection Infusion procedures Knowledge Lentivirus Infections Life MHC Class I Genes Macaca mulatta Mediating Medicine Methods Microbiology Monoclonal Antibodies Parasites Parasitology Pathology Patients Phase Plasma Plasmids Population Population Heterogeneity Prophylactic treatment Recording of previous events Research Research Personnel Role SIV Subfamily lentivirinae System T-Lymphocyte Testing Time Vaccine Design Vaccine Production Vaccines Variant Viral Viral Load result Viremia Virus career day env Gene Products neutralizing antibody pressure protective effect reconstitution research study response simian human immunodeficiency virus skills vaccinia virus vector virology

项目摘要

DESCRIPTION (provided by applicant): Project Summary: My research career goals are to continue to conduct extramurally-funded lentiviral research that addresses important knowledge gaps in both equine and human medicine. Although I have made progress towards accomplishing my goals, my ability to achieve independence as an investigator would be significantly enhanced by this award. The majority of my time will be spent conducting research that dissects the mechanisms of adaptive immune control of EIAV, and I plan to spend a significant amount of time acquiring new research skills and knowledge through collaborations with senior investigators in the Department of Veterinary Microbiology and Pathology. The department has an exceptionally talented group of research faculty, with a long history of acquiring extramural support. The major research focus is infectious diseases (host-parasite interactions) including virology, parasitology, bacteriology, vaccine production, and immunology. The overall goals of the proposed research are to develop immunization methods that induce protective antilentiviral CTL responses in individuals with diverse MHC class I backgrounds, and to define the correlates for neutralizing antibody-mediated protection against continued lentivirus replication. The lentiviral system under study is EIAV in horses. The experiments outlined in this application will first determine if a DNA vaccine encoding conserved Gag-specific epitope clusters, augmented with a plasmid expressing an equine IL-2/lgG fusion protein and followed by a vaccinia vector boost, will induce protective high avidity Gag-specific CTL in horses with diverse MHC class I alleles. Because our vaccine constructs will not encode envelope proteins, protective effects will occur in the absence of neutralizing antibody. Separately, we will identify viral envelope variants that arise during progressive EIAV infection, and we will produce equine monoclonal antibodies (EmAb) that neutralize these variants. We will then determine the requirements for neutralizing antibody-mediated protection by infusing combinations of neutralizing EmAbs to SCID foals, 10 and 14 days post-ElAV challenge. This time frame is relevant to post-HIV-1 exposure prophylaxis, and has been shown in B cell depletion studies to be the time when neutralizing antibodies are involved in SIV control. The equine SCID defect allows the protective effects of neutralizing antibodies directed against multiple naturally-occurring lentivirus escape variants to be tested without the influence of endogenous B and T cell responses. These are experiments that cannot be done in any other lentivirus model system. Relevance: Accomplishing these aims should help define the correlates for CTL- and neutralizing antibody-mediated protection against a naturally-occurring lentivirus infection in a diverse population. The information obtained from the proposed studies should have implications for HIV-1 vaccine design, where experiments of this type are not possible.

描述（由申请人提供）：项目摘要：我的研究职业目标是继续进行外部资助的慢病毒研究，以解决马和人类医学的重要知识差距。尽管我在实现目标方面取得了进展，但该奖项将大大增强我作为调查员实现独立的能力。我的大部分时间将用于剖析 EIAV 适应性免疫控制机制的研究，我计划花费大量时间通过与兽医微生物学和病理学系的高级研究人员合作来获取新的研究技能和知识。该系拥有一支才华横溢的研究人员队伍，长期以来一直获得校外支持。主要研究重点是传染病（宿主与寄生虫的相互作用），包括病毒学、寄生虫学、细菌学、疫苗生产和免疫学。拟议研究的总体目标是开发免疫方法，在具有不同 MHC I 类背景的个体中诱导保护性抗慢病毒 CTL 反应，并定义中和抗体介导的针对持续慢病毒复制的保护的相关性。正在研究的慢病毒系统是马的 EIAV。本申请中概述的实验将首先确定编码保守的 Gag 特异性表位簇的 DNA 疫苗，用表达马 IL-2/IgG 融合蛋白的质粒增强，然后进行牛痘载体加强，是否会诱导保护性高亲和力 Gag-具有多种 MHC I 类等位基因的马的特定 CTL。由于我们的疫苗结构不会编码包膜蛋白，因此在没有中和抗体的情况下会产生保护作用。另外，我们将鉴定进行性 EIAV 感染过程中出现的病毒包膜变异，并生产中和这些变异的马单克隆抗体 (EmAb)。然后，我们将在 ElAV 攻击后 10 天和 14 天，通过向 SCID 小马驹输注中和 EMAb 组合来确定中和抗体介导的保护的要求。该时间范围与 HIV-1 暴露后预防相关，并且 B 细胞耗竭研究已表明，该时间范围是中和抗体参与 SIV 控制的时间。马的 SCID 缺陷允许在不影响内源性 B 和 T 细胞反应的情况下测试针对多种天然慢病毒逃逸变体的中和抗体的保护作用。这些是在任何其他慢病毒模型系统中无法完成的实验。相关性：实现这些目标应有助于确定 CTL 和中和抗体介导的针对不同人群中自然发生的慢病毒感染的保护作用的相关性。从拟议的研究中获得的信息应该会对 HIV-1 疫苗的设计产生影响，而这种类型的实验是不可能的。