Respiratory Syncytial Virus Escape from Immunization

描述：（改编自申请人摘要）呼吸道合胞病毒 (RSV)是下呼吸道感染最常见的病毒因子， 婴儿，并在一生中重复感染。RSV抗原变异性 可能有助于RSV引起反复感染的能力。RSV也是 骨髓移植（BTM）中显著发病率和死亡率的原因 患者针对RSV的中和抗体可以预先存在于和/或可以是 被动给予BMT患者。据推测，由于 RSV抗体的选择性压力将累积F和G的变化 在免疫功能低下的患者中延长复制期间的蛋白质。顺序 将监测来自BMT患者的RSV分离株是否发生F 和/或G蛋白遗传变化，这些遗传变化与对 抗体可能导致复制适应性受损。因此抗体 耐药病毒将被表征为它们的复制适应性， 细胞培养和在动物中（目的2）。变异病毒逃避 还将测定动物的被动免疫（目标3）。在临床 RSV肺炎的BMT试验患者将接受人源化F 单克隆抗体（帕利珠单抗）。这将导致RSV的复制 在一种抗体存在的情况下，这种抗体已知可以选择逃避突变体。 因此，将在细胞培养物中选择帕利珠单抗逃逸突变体（Aim 4）， 以适应性和逃避被动免疫的能力为特征， 人源性病毒所描述的方式。这些实验将定义 RSV在长时间感染期间对抗体产生耐药性的程度 在免疫受损宿主中复制。此外， 细胞培养中产生的抗性病毒将保持正常的适应性， 将测定动物中的复制和逃避被动免疫。这些 研究将提供来自人类和动物的证据， 抗体抗性病毒可能对目前的被动免疫系统构成的挑战 针对RSV的免疫方法。

DESCRIPTION: (Adapted from Applicant's Abstract) Respiratory syncytial virus (RSV) is the most common viral agent of lower respiratory tract infections of infants and causes repeat infections throughout life. RSV antigenic variability may contribute to the ability of RSV to cause repeated infections. RSV is also a cause of significant morbidity and mortality in bone marrow transplant (BTM) patients. Neutralizing antibodies to RSV may be pre-existing in and/or may be passively administered to BMT patients. It is hypothesized that due to selective pressure by antibody RSV will accumulate changes in the F and G proteins during prolonged replication in immunocompromised patients. Sequential RSV isolates from BMT patients will be monitored for the development of F and/or G protein genetic changes that are associated with resistance to antibody may result in impaired fitness for replication. Therefore the antibody resistant viruses will be characterized as to their fitness for replication in cell culture and in animals (Aim 2). The ability of the mutant viruses to evade passive immunity in animals will also be determined (Aim 3). In a clinical trial BMT patients with RSV pneumonia will receive therapy with a humanized F monoclonal antibody (palivizumab). This will result in the replication of RSV in the presence of an antibody that is known to select for escape mutants. Thus, palivizumab escape mutants will be selected in cell culture (Aim 4) and characterized as to fitness and capacity to evade passive immunity in the manner described for the human derived viruses. These experiments will define the extent to which RSV becomes resistant to antibodies during prolonged replication in immunocompromised host. In addition, the likelihood that resistant viruses derived in cell culture will maintain normal fitness for replication and escape passive immunity in animals will be determined. These studies will provide evidence from humans and from animals as to the clinical challenges that antibody resistant viruses may pose to the current passive immunization approaches against RSV.