Down-regulation of MHC class l molecules by HCMV US2

人巨细胞病毒（HCMV）是一种β-疱疹病毒，可以建立持久性和潜伏性感染。 巨细胞病毒可导致免疫功能低下的个体，如移植受体的发病率和死亡率 和艾滋病毒感染者。事实上，HIV阳性患者有患HCMV相关性失明的风险。HCMV也是 新生儿出生缺陷的主要传染性原因，导致听力障碍和轻度精神障碍。 迟钝免疫系统对病毒的选择性压力导致了它们产生 躲避免疫检测的策略HCMV表达调节先天性和先天性巨噬细胞的蛋白质， 免疫系统的适应性分支。细胞免疫似乎是HCMV的主要靶点， 强调干扰CD 8+细胞毒性T细胞（CTL）活化。HCMV编码的基因产物来自 基因组US 2、US 3、US 6和US 11的独特短区域干扰HCMV的CTL识别， 通过阻止I类主要组织相容性复合体（MHC）的表面表达， 分子。这种策略将限制在HCMV感染的早期阶段针对HCMV表位的CTL的频率。 HCMV感染的早期阶段，使HCMV逃避免疫检测。US 2和US 11目标I类 蛋白酶体降解的分子。最近的证据表明，US 2也可能针对MHC类 II DRa和DMa分子用于蛋白酶体降解。这表明US 2是一个重要的基因， 调节免疫系统的HCMV病毒蛋白库。为此，我们将定义具体的 US 2的区域负责靶向MHC I类分子进行破坏并识别细胞 促进降解过程的蛋白质。我们将模拟HCMV感染的早期阶段， 确定US 2在其他病毒基因产物如US 3和US 11中的功能。全 了解HCMV US 2如何操纵宿主的细胞机制，以防止MHC I类， II类抗原呈递可允许设计阻断US 2功能的药剂。

Human cytomegalovirus (HCMV) is a (3-herpes virus that can establish persistence and latent infections. HCMV can cause morbidity and mortality in immuno-compromised individuals such as transplant-recipients and HIV-infected persons. In fact, HIV-positive patients are at risk of HCMV-related blindness. HCMV is also a major infectious cause of birth defects in newborns causing hearing disturbances and mild forms of mental retardation. Selective pressure by the immune system on viruses has resulted in their ability to generate evasive tactics to avoid immune detection. HCMV expresses proteins that modulate both the innate and adaptive branches of the immune system. Cellular immunity appears to be the main target of HCMV with an emphasis on interfering with CD8+ cytotoxic T cell (CTL) activation. HCMV encoded gene products from the unique short region of the genome US2, US3, US6 and US11 interfere with CTL recognition of HCMV- infected cells by preventing the surface expression of major histocompatibility complex (MHC) class I molecules. This strategy would limit the frequency of CTLs directed against HCMV epitopes during the early- phase of HCMV infection and allow HCMV to escape immune detection. US2 and US11 target class I molecules for proteasomal degradation. Recent evidence suggests that US2 may also target the MHC class II DRa and DMa molecules for proteasomal degradation. This suggests that US2 is an important gene in the HCMV repertoire of viral proteins that modulates the immune system. To that end, we will define the specific regions of US2 responsible for targeting MHC class I molecules for destruction as well as identify the cellular proteins that facilitates in the degradation process. We will mimic the early phase of HCMV infection and determine the function of US2 in the context of other viral gene products such as US3 and US11. A full understanding of how HCMV US2 manipulates the cellular machinery of the host to prevent MHC class I and class II antigen presentation may permit the design of pharmaceutical agents that block US2 function.