Role of Viral Chemokine Receptors in Cytomegalovirus Latency.

描述（由申请人提供）：人巨细胞病毒（HCMV）潜伏期再激活是骨髓移植患者中最常见的感染性并发症，具有显著的发病率和死亡率。关于长期HCMV感染建立和维持的病毒/宿主相互作用所知甚少。长期目标是确定导致巨细胞病毒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祖髓系细胞潜伏期建立中的作用，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，这有助于在体内感染期间建立潜伏期。项目总结：我们的假设是基于强有力的初步数据，这些数据表明缺乏M33的小鼠巨细胞病毒（MCMV）不能有效地建立潜伏感染，而表达hcmv编码的趋化因子受体UL33或US28的M33缺陷病毒在体内弥补了这种潜伏缺陷。研究将有三个具体目标：1)确定需要M33在体内建立和/或维持CMV潜伏期的髓系细胞类型，2)确定M33在单核细胞感染过程中的作用机制，以及3)确定M33介导的CMV潜伏期建立和/或维持所需的信号通路。本研究将利用特定的M33突变病毒结合微阵列分析来识别由M33和US28调节的信号通路。该方法是创新的，并使用多方面的方法来确定参与建立和/或维持髓系细胞中巨细胞病毒潜伏期的宿主和病毒因素。这项研究具有重要意义，因为它有望导致旨在预防巨细胞病毒潜伏期和潜在巨细胞病毒再激活引起的并发症的治疗策略的发展。与公共卫生相关：获得的新知识将有助于预防免疫功能低下患者的巨细胞病毒潜伏期和再激活，如移植患者、新生儿和艾滋病患者，这些患者的巨细胞病毒感染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. PUBLIC HEALTH RELEVANCE: Relevance to Public Health: The new knowledge obtained will lead to the prevention of CMV latency and reactivation in immunocompromised patients, such as transplant patients, neonates, and AIDS patients, where CMV infection leads to significant morbidity and mortality.