Down-regulation of MHC class l molecules by HCMV US2

描述(由申请人提供)：人类巨细胞病毒(HCMV)是一种可建立持续性和潜伏性感染的贝塔疱疹病毒。巨细胞病毒可导致免疫受损的个人，如移植受者和艾滋病毒感染者的发病率和死亡率。事实上，艾滋病毒阳性患者面临着与巨细胞病毒相关的失明风险。巨细胞病毒也是新生儿出生缺陷的主要感染性原因，导致听力障碍和轻度精神发育迟滞。免疫系统对病毒的选择性压力导致它们能够产生躲避免疫检测的策略。巨细胞病毒表达调节免疫系统固有分支和适应性分支的蛋白质。细胞免疫似乎是HCMV的主要靶点，重点是干扰CD8+细胞毒性T细胞(CTL)的激活。人巨细胞病毒US2、US3、US6和US11基因短区编码的基因产物通过抑制主要组织相容性复合体(MHC)I类分子的表面表达，干扰了HCMV感染细胞的CTL识别。这一策略将在巨细胞病毒感染的早期阶段限制针对巨细胞病毒表位的CTL的频率，并允许巨细胞病毒逃避免疫检测。US2和US11靶向蛋白酶体降解的I类分子。最近的证据表明，US2还可能针对MHC II类DRpha和DMalpha分子进行蛋白酶体降解。这表明US2是调节免疫系统的巨细胞病毒蛋白谱系中的一个重要基因。为此，我们将定义US2中负责破坏MHC I类分子的特定区域，并确定促进降解过程的细胞蛋白质。我们将模拟HCMV感染的早期阶段，并在其他病毒基因产物如US3和US11的背景下确定US2的功能。充分了解HCMV US2如何操纵宿主的细胞器来阻止MHC I类和II类抗原递呈，可能会使设计出阻断US2功能的药物成为可能。

DESCRIPTION (provided by the applicant): Human cytomegalovirus (HCMV) is a beta-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 DRalpha and DMalpha 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 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.