Vaccines and Antivirals for Arenaviruses

沙粒病毒是啮齿动物传播的病原体，在人类中引起显著的发病率和死亡率。 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）、朱宁病毒（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）。在人类感染旧大陆沙粒病毒LCMV或LASV后，细胞免疫在病毒清除和保护性免疫中起关键作用。因此，重要的是开发用于测量在人类感染背景下或响应于疫苗候选物的细胞介导的免疫应答的灵敏试剂。需要鉴定HLA限制性表位以开发可用于确定免疫应答的质量、定义保护和免疫病理学的相关性并最终指导候选疫苗的选择的测定。 为了从病原体中鉴定人CD 8 + T细胞表位，我们建立了一种方法， 利用生物信息学预测来鉴定候选表位，体外MHC结合测定和体内 在HLA转基因小鼠中进行免疫原性研究以验证表位，并进行疫苗接种研究以评估 表位是否对病毒攻击具有保护性。在过去的几年里，我们使用这种方法来 鉴定来自LCMV的第一个人CD 8 + T细胞表位（1，2，3）。在随后的研究中，我们已经表明，用这些表位之一GPC[447，455]免疫HLA-A2转基因小鼠，导致LCMV攻击后病毒滴度显著降低，并保护动物免受致死性疾病的影响。

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.