Respiratory Syncytial Virus Escape from Immunization

描述：(改编自申请者摘要)呼吸道合胞病毒 呼吸道合胞病毒(RSV)是鸡下呼吸道感染最常见的病原体。 并导致终生反复感染。呼吸道合胞病毒抗原变异性 可能有助于RSV引起反复感染的能力。RSV也是 骨髓移植(BTM)的重要致病和死亡原因 病人。RSV的中和抗体可能预先存在于和/或可能是 对骨髓移植患者被动给药。据推测，由于 RSV抗体的选择压力会累积F和G的变化 免疫受损患者在长时间复制过程中的蛋白质。序贯 将监测骨髓移植患者的RSV分离株是否会发展为F 和/或与抗病相关的G蛋白基因改变 抗体可能导致复制的适合性受损。因此，抗体 耐药病毒的特征是它们是否适合在 细胞培养和动物体内(目标2)。变异病毒逃避的能力 还将确定动物的被动免疫(目标3)。在临床上 患有呼吸道合胞病毒肺炎的骨髓移植试验患者将接受人性化F-F治疗 单抗(Palivizumab)。这将导致RSV的复制 在已知选择逃逸突变体的抗体存在的情况下。 因此，将在细胞培养中选择palivizumab逃逸突变体(目标4)和 以适应和逃避被动免疫的能力为特征的 描述人类衍生病毒的方式。这些实验将定义 RSV在长时间内对抗体产生抵抗力的程度 在免疫受损的宿主中复制。此外，有可能 在细胞培养中产生的耐药病毒将保持正常的适应能力 将确定在动物体内复制和逃避被动免疫。这些 研究将提供来自人类和动物的临床证据。 抗体抗性病毒可能对当前被动的 针对RSV的免疫接种方法。

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.