Immune Response to Polyomavirus Infection

描述(由申请人提供)：多瘤病毒BK(BKV)感染的抗体见于大多数健康成年人。病毒的重新激活发生在免疫抑制的患者身上。在国家数据库中，4.6%至9.2%的美国肾移植患者并发BKV肾病或BK病毒血症，需要治疗干预。BKV还会导致出血性膀胱炎，这需要在大约5%的造血干细胞移植接受者中进行临床干预。这笔赠款将阐明对BKV感染的体液和细胞免疫反应。这项工作可以总结为三个具体目标：第一个具体目标是进行前瞻性的纵向监测研究，以确定BKV中和抗体是否能预防BK病毒尿症、病毒血症和肾病。现有的关于这一主题的研究都是描述性的，没有适当的设计来确定抗BKV抗体是否真的有助于感染的解决。此外，到目前为止，研究还没有考虑到感染菌株的基因。后一种考虑很重要，因为BKV已知有四种主要的基因类型I、II、III和IV。拟议工作的第二个具体目标将是确定介导对BKV的保护性免疫的病毒靶点和T细胞的细胞表型。在前瞻性纵向监测研究过程中收集的血液样本将被用来表征对该病毒的细胞介导的免疫反应。患者的淋巴细胞将被单独的BKV基因或多肽刺激。将测量免疫细胞表面标志物和细胞内细胞因子的变化。第三个特定目标将确定多种感染基因和准种在BKV感染的免疫生物学中的作用。最近的研究表明，被多种BK病毒株感染是常见的。有必要进行进一步的研究，以确定这一观察的生物学和临床意义。因此，这一部分 该项目的一部分将寻求测量BK病毒载量、病毒基因型、遗传多样性和准种复杂性的变化，这些变化与BKV致敏T细胞的抗体滴度和频率的变化一起发生。这项研究将确定与多种基因类型或突变菌株的混合感染是否会改变临床结果。与公共卫生相关：对BKV感染的免疫反应的研究对于设计主动和被动抗体或细胞疫苗非常重要，这些疫苗每年可能使大约100,000名移植患者受益。此外，通过研究BKV所产生的知识将与了解对其他几种在人类中广泛流行的多瘤病毒的免疫反应有关，包括多瘤病毒JC、WI和KU、默克尔细胞病毒和棘毛状毛发育不良病毒。

DESCRIPTION (provided by applicant): Antibodies to Polyomavirus BK (BKV) infection are seen in the majority of healthy adults. Reactivation of the virus occurs in immunosuppressed patients. In national databases, 4.6 to 9.2% of U.S. kidney transplants are complicated by BKV-nephropathy or BK viremia that requires therapeutic intervention. BKV also causes hemorrhagic cystitis which requires clinical intervention in about 5% of hematopoietic stem cell transplantation recipients. This grant will elucidate the humoral and cellular immune response to BKV infection. The work proposed work can be summarized in the form of 3 specific aims The first specific aim is to perform prospective longitudinal monitoring studies to determine if genotype- specific BKV neutralizing antibodies protect against BK viruria, viremia and nephropathy. Existing studies on the subject have been descriptive and not appropriately designed to determine if anti-BKV antibodies actually help in the resolution of infection. Furthermore, studies to date have not accounted for the genotype of the infecting strain. The latter consideration is important because BKV is known to have four major genotypes I, II, III, and IV. The second specific aim of the proposed work will be to determine the viral targets and cellular phenotypes of T-cells that mediate protective immunity against BKV. Blood samples collected during the course of a prospective longitudinal monitoring study will be used to characterize the cell-mediated immune responses to this virus. Patient lymphocytes will be stimulated by individual BKV genes or peptides. Changes in immunologic cell surface markers and intra-cellular cytokines will be measured. The third specific aim will determine the role of multiple infecting genotypes and quasispecies in the immunobiology of BKV infection. Recent work has shown that infection by multiple BK virus strains is common. Further studies are warranted to determine the biologic and clinical implications of this observation. Hence, this part of the project will seek to measure changes in BK virus load, viral genotype, genetic diversity, and quasispecies complexity that occur in conjunction with alterations in antibody titer and frequency of BKV sensitized T-cells. The study will determine if coinfection with multiple genotypes or mutant strains alters the clinical outcome. Relevance to Public Health: A study of the immune response to BKV infection is important to design active and passive antibody or cell based vaccines with the potential to benefit approximately 100,000 transplant patients annually. In addition, the knowledge generated by studying BKV will be relevant to understanding the immune response to several other polyomaviruses widely prevalent in man, including polyomaviruses JC, WI, and KU, Merkel cell virus, and Trichodysplasia spinulosa virus.