BIOLOGY OF CYTOMEGALOVIRUS INFECTION IN BONE MARROW TRANSPLANTATION

这是一个研究糖尿病发病机制的项目的继续。 骨髓移植后人巨细胞病毒感染 (BMT)。尽管巨细胞病毒相关死亡率已显著降低，但巨细胞病毒 我们37%的异基因骨髓移植患者继续发生肺部感染 接受者，以及与长期抗病毒治疗相关的发病率 表明目前的管理方法并不是最优的。这 该项目将基础研究与临床研究相结合，试图 进一步了解巨细胞病毒感染的性质，并改善 治疗。在过去的四年里，基础研究部分 完成了几个CMV Towne基因的克隆和结构鉴定 在此期间开发的被膜蛋白和病毒试剂正在 适用于本续集项目IV和V中的疫苗开发。 巨细胞病毒与细胞表面肽酶相互作用的研究， CD13/氨基肽酶N(CD13/APN)，将形成基础研究部分 这个续集。该项目的临床研究已成为基础 在该计划内进行CMV抗病毒试验，并开创了 更昔洛韦在骨髓移植中的先发制人应用。在接下来的时间里，我们将 用基于聚合酶链式反应的巨细胞病毒检测方法评估巨细胞病毒的半定量检测 血浆中DNA与预期血液和支气管肺泡的比较 用于骨髓移植受者抗病毒治疗的灌洗培养。 该项目最近的一个主要成就是观察到 CD13/APN增加细胞对可溶性CMV感染的敏感性 CD13/APN可中和CMV。此外，CD13/APN存在于CMV上 病毒粒子，抗CD13/APN抗体能有效中和病毒。角色 CD13/APN在CMV与细胞结合、融合及相互作用中的作用 糖蛋白和CD13/APN将被研究。此外，这种蛋白质 病毒抑制所需的CD13/APN结构域(S)将被确定， 并将开发具有抗病毒潜力的CD13/APN可溶性形式。 CD13/APN存在于肠、肾、肝、肺、血管内皮细胞， 还有大脑--所有CMV营养丰富的区域。此外，CD13/APN 在血浆中循环，并可能参与巨细胞病毒的某些方面 疾病发病机制。我们假设CD13/APN在之前 在CMV与受感染宿主的相互作用中的未知角色 利用正在进行的骨髓移植受者研究来评估 在临床研究中检测血浆CD13/APN水平的可能性 在CMV感染期间。

This is a continuation of a project which investigates the pathogenesis of human cytomegalovirus (CMV) infection after bone marrow transplantation (BMT). Although CMV-related mortality has been markedly reduced, CMV pulmonary infection continues to occur in 37% of our allogeneic BMT recipients, and the morbidity associated with prolonged antiviral treatment suggests that the current methods of management are not optimal. This project combines basic research with clinical studies in an attempt to better understand the nature of CMV infection and to improve such treatment. In the past four years, the basic research portion has completed the cloning and structural characterization of several CMV Towne tegument proteins, and viral reagents developed during this time are being applied to vaccine development in projects IV and V of this continuation. A study of the interaction between CMV and the cell surface peptidase, CD13/aminopeptidase N (CD13/APN), will form the basic research portion of this continuation. The clinical studies of the project have been the abase for the CMV antiviral trials within the Program and pioneered the preemptive use of ganciclovir in BMT. In the continuation, we will evaluate a semiquantitative measure of CMV, using a PCR-based assay of CMV DNA in plasma, in comparison with prospective blood and bronchoalveolar lavage cultures for utility in antiviral management of BMT recipients. A major recent accomplishment of this project has been the observation that CD13/APN increases cell susceptibility to CMV infection that soluble CD13/APN can neutralize CMV. In addition, CD13/APN is present on CMV virions, and antibody to CD13/APN efficiently neutralizes virus. The role of CD13/APN in CMV binding and fusion to cells and the interaction of CMV glycoproteins and CD13/APN will be investigated. In addition, the protein domain(s) of CD13/APN necessary for virus inhibition will be determined, and soluble forms of CD13/APN having antiviral potential will be developed. CD13/APN is present inc ells of the gut, kidneys, liver, lung, endothelium, and brain--all regions for which CMV is trophic. In addition, CD13/APN circulates in the plasma and might be involved in some aspect of CMV disease pathogenesis. We hypothesize that CD13/APN plays a previously unrecognized role in the interaction of CMV with the infected host and will utilize the ongoing studies in marrow transplant recipients to evaluate this possibility in clinical studies measuring plasma levels of CD13/APN during CMV infection.