Role of Viral Chemokine Receptors in Cytomegalovirus Latency

项目摘要/摘要 人巨细胞病毒(HCMV)从潜伏期重新激活是最常见的 骨髓移植患者的感染性并发症，发病率和 死亡率。人们对病毒/宿主之间的相互作用知之甚少 建立和维持长期的人巨细胞病毒感染。长期目标是 确定导致CMV潜伏期发展的病毒和宿主机制。 这项建议的目的是确定CMV编码的趋化因子的作用 受体在祖细胞髓系细胞潜伏期的建立和 确定促进CMV潜伏期建立的宿主信号通路。这个 中心假设是巨细胞病毒编码的趋化因子受体激活宿主信号 在体内感染期间帮助建立潜伏期的途径。项目 摘要：我们的假设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 表达HCMV编码的趋化因子受体UL33或 US28，补充了体内的这一潜伏期缺陷。将追求三个具体目标：1) 确定需要M33建立和/或建立的髓系细胞类型 体内CMV潜伏期的维持，2)确定潜在的作用机制 M33在单核细胞感染过程中的作用，以及3)识别M33介导的信号通路 (S)建立和/或维护巨细胞病毒潜伏期所需。这一目标将利用 特定M33突变病毒与微阵列分析相结合以识别信号 受M33和US28调制的通路。这种方法是创新的，并使用 一个多方面的方法，以确定宿主和病毒因素参与建立 和/或维持髓系细胞中的CMV潜伏期。这个 提出的研究具有重要意义，因为它有望导致 旨在预防CMV潜伏期和因以下原因引起的并发症的治疗策略 潜伏的巨细胞病毒重新激活。与公共卫生的相关性：获得的新知识 会导致预防CMV潜伏期和免疫功能受损的重新激活 患者，如移植患者、新生儿和艾滋病患者，其中CMV感染 导致严重的发病率和死亡率。

Project Summary/Abstract 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.