Role of Viral Chemokine Receptors in Cytomegalovirus Latency.

描述(由申请人提供)：人巨细胞病毒(HCMV)潜伏期重新激活是骨髓移植患者最常见的感染性并发症，具有显著的发病率和死亡率。关于病毒/宿主之间的相互作用控制着人类巨细胞病毒长期感染的建立和维持，人们知之甚少。长期目标是确定导致CMV潜伏期发展的病毒和宿主机制。本研究的目的是确定CMV编码的趋化因子受体在建立祖细胞系髓系细胞潜伏期中的作用，并确定促进CMV潜伏期建立的宿主信号通路。中心假设是CMV编码的趋化因子受体激活宿主信号通路，帮助建立体内感染期间的潜伏期。项目摘要：我们的假设建立在强大的初步数据基础上，这些数据表明，缺乏M33的小鼠CMV(MCMV)不能有效地建立潜伏感染，并且表达HCMV编码的趋化因子受体UL33或US28的M33缺陷病毒在体内补充了这一潜伏缺陷。我们将追求三个特定的目标：1)鉴定建立和/或维持体内巨细胞病毒潜伏期需要M33的髓系细胞类型；2)鉴定M33在单核细胞感染过程中所起作用的机制；3)鉴定建立和/或维持巨细胞病毒潜伏期所需的M33介导的信号通路(S)。这一目标将利用特定的M33突变病毒结合微阵列分析来识别由M33和US28调制的信号通路。该方法是创新的，使用多方面的方法来识别在髓系细胞中建立和/或维持CMV潜伏期所涉及的宿主和病毒因素。这项拟议的研究具有重要意义，因为它有望导致旨在预防CMV潜伏期和因潜伏性CMV重新激活而引起的并发症的治疗策略的发展。与公共卫生相关：获得的新知识将导致预防免疫低下患者的CMV潜伏和重新激活，如移植患者、新生儿和艾滋病患者，在这些患者中，CMV感染会导致显著的发病率和死亡率。

DESCRIPTION (provided by applicant): Reactivation of Human Cytomegalovirus (HCMV) from latency is the most common infectious complication in bone marrow transplant patients, with significant morbidity and mortality. Very little is known about the viral/host interactions governing the establishment and maintenance of long term HCMV infection. The long-term goal is to identify the viral and host mechanisms that lead to the development of CMV latency. The objective of this proposal is to determine the role of the CMV-encoded chemokine receptors in the establishment of latency in progenitor myeloid lineage cells and to identify the host signaling pathways that promote CMV establishment of latency. The central hypothesis is that the CMV-encoded chemokine receptors activate host signaling pathways which aid in the establishment of latency during in vivo infection. Project Summary: Our hypothesis is based on strong preliminary data which demonstrates that murine CMV (MCMV) lacking M33 does not efficiently establish latent infection and that M33-deficient viruses which express the HCMV-encoded chemokine receptors, UL33 or US28, complements this latency defect in vivo. Three specific aims will be pursued: 1) Identify the myeloid lineage cell type which requires M33 for the establishment and/or maintenance of CMV latency in vivo, 2) Identify the mechanisms underlying the role of M33 during infection in monocytes, and 3) Identify the M33-mediated signaling pathway (s) required for establishment and/or maintenance of CMV latency. This aim will utilize specific M33 mutant viruses coupled with microarray analysis to identify signaling pathways which are modulated by M33 and US28. The approach is innovative, and uses a multifaceted approach to identify the host and viral factors involved in the establishment and/or maintenance of CMV latency in myeloid lineage cells. The proposed research is significant, because it is expected to lead to the development of therapeutic strategies aimed at preventing CMV latency and complications due to reactivation of latent CMV. Relevance to Public Health: The new knowledge obtained will lead to the prevention of CMV latency and reactivation in immunocompromised patients, such transplant patients, neonates, and AIDS patients, where CMV infection leads to significant morbidity and mortality.