Dissecting the Human Antibody Response to Dengue Virus

描述（由申请人提供）：登革热是人类最重要的节肢动物传播病毒感染。在自然感染和疫苗接种的情况下，人抗体对于清除登革病毒（DENV）是必需的。巧合的是，在某些条件下，抗体也可以增强DENV感染细胞的能力，并且已经证明抗体在登革热的动物模型中加重疾病。尽管有证据表明抗体在登革发病机制中很重要，但关于人抗体应答DENV的结合和功能特性知之甚少。考虑到全球登革热问题的规模，这是我们知识中的一个显著空白。基于我们小组的初步研究，在此我们提出检验这样的假设，即病毒蛋白在病毒表面的组装和紧密包装产生的新表位是功能重要的人抗体应答的主要靶点。这项工作的影响将是广泛的，因为它将重新定向一个主要集中在E蛋白亚基上的B细胞表位的领域，以考虑病毒组装后产生的新结构特征和表位。我们的研究分为以下目标。在目标1中，我们将确定人免疫血清中中和抗体识别的主要抗原和表位。在目的2中，我们将检验人免疫血清中DENV增强抗体主要靶向病毒前膜蛋白的假设。这项工作的重要性很高，因为这些研究与开发新疫苗和评估目前进入临床试验的疫苗直接相关。

DESCRIPTION (provided by applicant): Dengue is the most significant arthropod-transmitted viral infection of humans. Both in the context of natural infection and vaccination, human antibodies are necessary for clearing dengue virus (DENV). Paradoxically, under some conditions antibodies can also enhance the ability of DENV to infect cells and antibodies have been demonstrated to exacerbate disease in animal models of dengue. Despite the evidence that antibodies are important in dengue pathogenesis, very little is known about the binding and functional properties of the human antibody response to DENV. This is a remarkable gap in our knowledge given the scale of the global dengue problem. Based on preliminary studies from our group, here we propose to test the hypothesis that new epitopes created by the assembly and close packing of viral proteins on the surface of the virus are the main targets of the functionall important human antibody response. The impact of this work will be far ranging as it will redirect a field that has mainly focused on B-cell epitopes on subunits of E protein to consider new structural features and epitopes created following viral assembly. Our studies are divided into the following aims. In aim 1 we will define the main antigens and epitopes recognized by neutralizing antibodies in human immune serum. In aim 2 we will test the hypothesis that DENV enhancing antibodies in human immune serum mainly target the viral pre-membrane protein. The significance of the work is high because the studies are directly relevant to developing new vaccines and for evaluating current vaccines entering clinical trials.