Vaccines and Antivirals for Arenaviruses

沙粒病毒疫苗和抗病毒药物

• 批准号: 8260251
• 负责人: Michael Joseph Buchmeier
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260251
• 关键词: Animals; Antiviral Agents; Arenavirus; Binding; Bioinformatics; Biological Assay; Bolivian Hemorrhagic Fever Virus; CD8B1 gene; Cellular Immunity; Development; Disease; Drug Delivery Systems; Emerging Communicable Diseases; Epitopes; Genome; Goals; Guanarito virus; HLA-A2 Antigen; Human; Immune response; Immunity; Immunization; In Vitro; Infection; Infectious Diseases Research; Junin virus; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Measures; Morbidity - disease rate; Old World Arenaviruses; Play; Reagent; Rodent; Role; T-Lymphocyte Epitopes; Transgenic Mice; Vaccination; Vaccines; Viral; Virus; biodefense; candidate selection; immunogenicity; immunopathology; in vivo; mortality; pathogen; response; vaccine candidate

Arena-viruses are rodent-borne pathogens that cause significant morbidity and mortality in humans. Pathogenic arenaviruses include Lassa (LASV), lymphocytic choriomeningitis (LCMV), Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV) and Whitewater Arroyo (WWAV) viruses. Following human infection with the Old World arenaviruses LCMV or LASV, cellular immunity plays a pivotal role in viral clearance and protective immunity. Therefore, it is important that sensitive reagents to measure the cellmediated immune response in the context of human infection or in response to vaccine candidates are developed. The identification of HLA-restricted epitopes is required to develop assays that can be used to determine the quality of immune responses, define correlates of protection and immunopathology, and ultimately guide the selection of candidate vaccines. In order to identify human CD8+ T cell epitopes from pathogens, we have established an approach that utilizes bioinformatic predictions to identify candidate epitopes, in vitro MHC binding assays and in vivo immunogenicity studies in HLA transgenic mice to validate epitopes, and vaccination studies to evaluate whether epitopes are protective against viral challenge. Over the few past years, we used this approach to identify the first human CD8+ T cell epitopes from LCMV (1,2,3). In subsequent studies we have shown that immunization of HLA-A2 transgenic mice with one of these epitopes, GPC[447,455] led to significant reductions in viral titer following challenge with LCMV and protected animals from lethal disease.

沙粒病毒是啮齿动物传播的病原体，可导致人类显着发病和死亡。 致病性沙粒病毒包括拉沙病毒(LASV)、淋巴细胞性脉络丛脑膜炎病毒(LCMV)、胡宁病毒(JUNV)、马丘波病毒(MACV)、瓜纳里托病毒(GTOV)、萨比亚病毒(SABV)和白水阿罗约病毒(WWAV)。人类感染旧世界沙粒病毒 LCMV 或 LASV 后，细胞免疫在病毒清除和保护性免疫中发挥着关键作用。因此，开发敏感试剂来测量人类感染或候选疫苗反应中细胞介导的免疫反应非常重要。需要鉴定 HLA 限制性表位来开发可用于确定免疫反应质量、定义保护和免疫病理学的相关性并最终指导候选疫苗选择的检测方法。 为了识别病原体中的人类 CD8+ T 细胞表位，我们建立了一种方法 利用生物信息学预测来识别候选表位、体外 MHC 结合测定和体内 HLA 转基因小鼠的免疫原性研究以验证表位，以及疫苗接种研究以评估 表位是否具有针对病毒攻击的保护作用。在过去的几年里，我们使用这种方法 从 LCMV 中鉴定出第一个人类 CD8+ T 细胞表位 (1,2,3)。在随后的研究中，我们表明，用这些表位之一 GPC[447,455] 对 HLA-A2 转基因小鼠进行免疫接种，可导致 LCMV 攻击后病毒滴度显着降低，并保护动物免受致命疾病的侵害。