BIOLOGY OF CYTOMEGALOVIRUS INFECTION IN BONE MARROW TRANSPLANTATION

这是一个项目的延续，该项目调查了 骨髓移植后巨细胞病毒感染 （BMT）。 虽然CMV相关的死亡率已显着降低， 肺部感染继续发生在37%的同种异体BMT 以及与长期抗病毒治疗相关的发病率 这表明目前的管理方法并不是最佳的。 这 该项目将基础研究与临床研究相结合， 更好地了解CMV感染的性质并改善这种情况 治疗 在过去的四年里，基础研究部分 完成了几个CMV Towne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被 适用于本延续项目IV和V的疫苗开发。 CMV与细胞表面肽酶相互作用的研究， CD 13/氨肽酶N（CD 13/APN），将构成基础研究部分， 这种延续。 该项目的临床研究已被广泛应用。 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优先使用。 在下一节中，我们将 使用基于PCR的CMV检测法评价CMV的半定量测量 血浆中的DNA，与预期血液和支气管肺泡中的DNA比较 灌洗培养物用于BMT接受者的抗病毒管理。 该项目最近的一项主要成就是观察到， CD 13/APN增加细胞对CMV感染的易感性，可溶性 CD 13/APN能中和CMV。 此外，CMV上存在CD 13/APN， 抗CD 13/APN抗体能有效中和病毒。 的作用 CD 13/APN在CMV与细胞结合和融合中的作用及CMV与细胞的相互作用 糖蛋白和CD 13/APN的研究。 此外，蛋白质 确定病毒抑制所必需的CD 13/APN的结构域， 并将开发具有抗病毒潜力的可溶形式的CD 13/APN。 CD 13/APN存在于肠、肾、肝、肺、内皮细胞， 和大脑--所有这些区域都是CMV的营养区。 此外，CD 13/APN 在血浆中循环，可能参与CMV的某些方面 发病机理 我们推测CD 13/APN在细胞凋亡中起着重要的作用。 在CMV与受感染宿主的相互作用中未被认识到的作用， 利用正在进行的骨髓移植受者研究， 在临床研究中测量血浆CD 13/APN水平的这种可能性 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.