Antibody inhibition of respiratory syncytial virus G protein activity

描述（由申请人提供）：呼吸道合胞病毒（RSV）是婴幼儿和老年人严重下呼吸道疾病的最重要原因。目前还没有安全有效的RSV疫苗。我们对RSV感染相关的免疫和疾病发病机制的理解的进展表明，RSV G蛋白含有一个CX3C趋化因子基序，该基序与CX3CR1趋化因子受体相互作用，改变CX3CL1的活性，并影响免疫和疾病发病机制的各个方面。RSV疫苗急性应答或自然感染诱导的G蛋白抗体抑制G蛋白CX3C-CX3CR1相互作用；然而，尚不清楚抗g蛋白抗体反应是否能防止疾病发病。我们的长期研究目标是确定RSV G蛋白中诱导保护性抗体反应的区域，阻断G蛋白CX3C-CX3CR1相互作用，为开发安全有效的RSV候选疫苗提供基础。我们的主要假设是，对G蛋白进行修饰，消除CX3C基序可以提高疫苗的安全性，而诱导阻断这种相互作用的抗体可以提高疫苗的效力。该提案将利用明确定义的CX3C趋化因子结合和白细胞迁移测定，抗G蛋白单克隆抗体面板，G蛋白肽和多肽面板以及明确定义的小鼠模型。使用这些试剂，我们将研究以下具体目标：1)确定G蛋白中诱导阻断G蛋白CX3C与CX3CR1结合的抗体的区域；2)确定阻断G蛋白CX3C与CX3CR1结合的抗体抑制与RSV感染或福尔马林灭活（FI-RSV）疫苗增强疾病相关的肺部炎症反应的能力；3)确定阻断G蛋白结合CX3CR1的抗体与人RSV疾病的白细胞迁移和严重程度之间的关系。这项拟议的研究具有创新性，因为它将确定RSV G蛋白中诱导抗体阻断RSV疾病的区域，并提供与抑制RSV G蛋白CX3C-CX3CR1相互作用相关的体液反应的关键信息，以预防疾病。

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV) is the most important cause of severe lower respiratory tract illness in infants and the elderly. Currently, no safe and efficacious RSV vaccine exists. Advances in our understanding of immunity and disease pathogenesis associated with RSV infection have revealed that RSV G protein contains a CX3C chemokine motif that interacts with the CX3CR1 chemokine receptor, modifies the activities of CX3CL1, and affects aspects of immunity and disease pathogenesis. Antibodies to G protein induced in the acute response to RSV vaccination or natural infection inhibit G protein CX3C-CX3CR1 interaction; however, it is unclear if anti-G protein antibody responses protect from disease pathogenesis. The long-term goal of our research is to determine the regions in RSV G protein that induce a protective antibody response which block G protein CX3C-CX3CR1 interaction to provide the foundation for the development of safe and efficacious RSV vaccine candidates. Our central hypothesis is that modifications to the G protein which eliminate the CX3C motif may improve vaccine safety while induction of antibodies that block this interaction may improve vaccine efficacy. The proposal will take advantage of a well-defined CX3C chemokine binding and leukocyte migration assay, panels of anti-G protein monoclonal antibodies, panels of G protein peptides and polypeptides, and well-defined mouse model. Using these reagents we will examine the following specific aims: 1) Determine regions in the G protein that induce antibodies which block G protein CX3C binding to CX3CR1; 2) Determine the ability of antibodies that block G protein CX3C binding to CX3CR1 to inhibit the pulmonary inflammatory response associated with RSV infection, or formalin- inactivated (FI-RSV) vaccine enhanced disease; 3) Determine the association between antibodies that block G protein binding to CX3CR1 and leukocyte migration and severity of RSV disease in humans. The proposed research is innovative because it will identify regions in the RSV G protein that induce antibodies which block RSV disease, and provide critical information on humoral responses associated with inhibiting RSV G protein CX3C-CX3CR1 interaction to prevent disease.