Vaccines and Antivirals for Arenaviruses

竞技场病毒是由啮齿动物传播的病原体，在人类中会导致严重的发病率和死亡率。 致病ArenaV包括Lassa(LASV)、淋巴细胞性脉络膜脑膜炎(LCMV)、Junin(JUNV)、Machupo(MACV)、Guanarito(GTOV)、Sabia(SABV)和白水Arroyo(WWAV)病毒。在人类感染旧大陆病毒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，重要的是开发灵敏的试剂来测量在人类感染或对候选疫苗的反应中的细胞介导的免疫反应。需要对人类白细胞抗原限制性表位进行鉴定，以确定免疫反应的质量，确定保护性和免疫病理学的相关性，并最终指导候选疫苗的选择。 为了从病原体中识别人类CD8+T细胞表位，我们建立了一种方法，即 利用生物信息学预测来确定候选表位，体外MHC结合分析和体内 在人类白细胞抗原转基因小鼠中进行免疫原性研究以验证表位，并进行疫苗研究以评估 表位是否对病毒挑战具有保护作用。在过去的几年里，我们使用这种方法来 从LCMV(1，2，3)中鉴定第一个人CD8+T细胞表位。在随后的研究中，我们已经证明，用这些表位之一GPC[447,455]免疫人类白细胞抗原A2转基因小鼠，可以显著降低LCMV攻击后的病毒滴度，并保护动物免受致命疾病的影响。

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.