Role of Viral Chemokine Receptors in Cytomegalovirus Latency

项目概要/摘要 人巨细胞病毒（HCMV）潜伏期的再激活是最常见的 骨髓移植患者感染并发症，发病率高， mortality.很少有人知道病毒/宿主的相互作用， HCMV长期感染的建立和维持。长期目标是 确定导致CMV潜伏期发展的病毒和宿主机制。 这个提议的目的是确定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中的作用， 确定促进CMV建立潜伏期的宿主信号通路。的 中心假设是CMV编码的趋化因子受体激活宿主信号传导 在体内感染期间帮助建立潜伏期的途径。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的鼠CMV（MCMV）不能有效地建立潜伏感染， 表达HCMV编码的趋化因子受体UL 33或 US 28补充了体内的这种潜伏缺陷。将追求三个具体目标：1） 鉴定需要M33建立的髓系细胞类型和/或 维持体内CMV潜伏期，2）确定 M33在单核细胞感染期间，和3）鉴定M33介导的信号传导途径 (s)建立和/或维持CMV潜伏期所需的。这一目标将利用 特异性M33突变病毒与微阵列分析结合以鉴定信号传导 由M33和US 28调节的通路。该方法是创新的，并使用 一个多方面的方法来确定主机和病毒因素参与建立 和/或维持骨髓谱系细胞中的CMV潜伏期。的 拟议的研究是重要的，因为它预计将导致发展 旨在预防CMV潜伏期和并发症的治疗策略， 潜伏CMV的再激活。与公共卫生的相关性：获得的新知识 将导致免疫功能低下的CMV潜伏期和再激活的预防 患者，如移植患者，新生儿和艾滋病患者，其中CMV感染 导致显著的发病率和死亡率。

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.