Antibody inhibition of respiratory syncytial virus G protein activity

描述（由申请方提供）：呼吸道合胞病毒（RSV）是婴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。我们对与RSV感染相关的免疫和疾病发病机制的理解进展表明，RSV G蛋白含有CX 3C趋化因子基序，其与CX 3CR 1趋化因子受体相互作用，修饰CX 3CL 1的活性，并影响免疫和疾病发病机制的各个方面。在对RSV疫苗接种或自然感染的急性应答中诱导的G蛋白抗体抑制G蛋白CX 3C-CX 3CR 1相互作用;然而，尚不清楚抗G蛋白抗体应答是否保护免于疾病发病机制。我们研究的长期目标是确定RSV G蛋白中诱导保护性抗体应答的区域，这些区域阻断G蛋白CX 3C-CX 3CR 1相互作用，为开发安全有效的RSV候选疫苗提供基础。我们的中心假设是，消除CX 3C基序的G蛋白修饰可能会提高疫苗的安全性，而诱导阻断这种相互作用的抗体可能会提高疫苗的效力。该提案将利用明确定义的CX 3C趋化因子结合和白细胞迁移试验、抗G蛋白单克隆抗体组、G蛋白肽和多肽组以及明确定义的小鼠模型。使用这些试剂，我们将检查以下特定目的：1）确定G蛋白中诱导阻断G蛋白CX 3C与CX 3CR 1结合的抗体的区域; 2）确定阻断G蛋白CX 3C与CX 3CR 1结合的抗体抑制与RSV感染或福尔马林灭活（FI-RSV）疫苗增强的疾病相关的肺部炎症反应的能力; 3）确定阻断G蛋白与CX 3CR 1结合的抗体与白细胞迁移和人类RSV疾病严重程度之间的关联。这项研究具有创新性，因为它将确定RSV G蛋白中诱导阻断RSV疾病的抗体的区域，并提供与抑制RSV G蛋白CX 3C-CX 3CR 1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.