Naturally occurring human antibodies to alphavirus infection

描述(申请人提供)：甲型病毒是节肢动物传播的病毒，在世界范围内引起具有重要医学意义的人类感染。缺乏针对这些病毒的特定疗法，而且只有实验性疫苗可用于这些感染。在这项开发/探索性资助中，我们将产生并详细描述人类抗甲型病毒抗体，填补我们对甲型病毒感染的人类抗体库知识的一个未解决的空白。虽然过去的研究已经确定了小鼠对典型甲型病毒的抗体反应，如辛德比斯病毒，但对人类对自然甲型病毒感染的特定表位或抗体谱系知之甚少。我们建议使用人类杂交瘤技术，该技术已被证明能够产生针对20世纪三种大流行病毒中的每一种的强大中和抗体，尽管这些病毒中的每一种都在多年前传播，以产生针对两种具有重要医学意义的甲型病毒的人类抗体，委内瑞拉马脑炎(VEE)和马亚罗(MAY)病毒。我们将从秘鲁甲型病毒流行地区的独特人群中采集血液，这些人已被明确诊断为最近感染了VEE或MAY病毒。从这些个体的B细胞中，我们将产生中和VEE和MAY病毒的人源单抗，并在体外和体内鉴定人源单抗。VEE和MAY病毒在拉丁美洲国家造成严重的发病率，并对美国构成威胁。仅VEE病毒一项就占某些热带地区假定的登革热病例的7%，被认为是NIAID B类优先病原体，而MAY病毒会导致可持续几个月的反复丧失能力的关节痛，类似于基孔肯雅病毒。这项研究的完成将产生第一个针对VEE和MAY病毒的自然产生的人类抗体，为了解这些重要的人类病原体的抗体谱系提供了洞察力。它还将寻求识别VEE和MAY病毒特异性和更广泛的交叉反应(对其他甲型病毒)抗体及其表位。这些抗体是潜在的治疗药物，关于它们的表位，特别是交叉反应表位的信息，可能建议优化疫苗方法，可能成功地针对多种甲型病毒。

DESCRIPTION (provided by applicant): Alphaviruses are arthropod-transmitted viruses that cause medically-important human infections worldwide. Specific therapeutics for these viruses are lacking, and only experimental vaccines are available for these infections. In this Developmental/Exploratory Grant, we will generate and characterize in detail human anti- alphavirus antibodies, filling an unaddressed gap in our knowledge regarding the human antibody repertoire to alphavirus infection. Although past studies have characterized antibody responses to prototypical alphaviruses, such as Sindbis virus, in mice; little is known regarding the specific epitopes or the repertoire of human antibodies to natural alphavirus infection. We propose to use human hybridoma technology that has proven capable of generating potent neutralizing antibodies to each of the three 20th century pandemic viruses, despite the fact that each of these viruses circulated many years ago, to generate human antibodies to two medically important alphaviruses, Venezuelan equine encephalitis (VEE) and Mayaro (MAY) virus. We will obtain blood from a unique population of individuals from endemic areas of alphavirus transmission in Peru who have been definitively diagnosed with recent VEE or MAY virus infection. From the B cells of these individuals, we will generate human monoclonal antibodies that neutralize VEE and MAY viruses, and we will characterize in vitro and in vivo the human monoclonal antibodies. VEE and MAY viruses cause significant morbidity in Latin American countries and also pose threats to the United States. VEE virus alone accounts for as much as 7% of the supposed dengue fever cases in certain tropical regions and is considered a NIAID Category B priority pathogen whereas MAY virus causes recurrent incapacitating arthralgias that can last several months, similar to Chikungunya virus. Completion of this study will generate the first naturally- occurring human antibodies to VEE and MAY virus, providing insight into the antibody repertoire toward these important human pathogens. It will also seek to identify VEE and MAY virus-specific and more broadly cross- reactive (to other alphaviruses) antibodies and their epitopes. Such antibodies are potential therapeutics, and information regarding their epitopes, particularly cross-reactive epitopes, may suggest optimized vaccine approaches that may successfully target multiple alphaviruses.