Down-regulation of MHC class l molecules by HCMV US2

HCMV US2 下调 MHC I 类分子

• 批准号: 7382429
• 负责人: Domenico Tortorella
• 金额: $ 5.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382429
• 关键词: Affinity; Antigen Presentation; Binding; Biochemical; Blindness; CD8B1 gene; Calmodulin; Cell Line; Cell physiology; Cells; Cellular Immunity; Class; Complex; Congenital Abnormality; Cystic Fibrosis; Cytomegalovirus; Cytomegalovirus Infections; Cytoplasmic Tail; Cytotoxic T-Lymphocytes; Detection; Down-Regulation; Endoplasmic Reticulum; Epitopes; Frequencies; Genes; Genome; HIV Seropositivity; Hearing; Herpesviridae; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Immune; Immune response; Immune system; Immunoblotting; Individual; Infection; Light; Major Histocompatibility Complex; Mediating; Mental Retardation; Methods; Molecular; Morbidity - disease rate; Mutagenesis; Newborn Infant; Patients; Persons; Pharmacologic Substance; Phase; Process; Proteins; Pulmonary Emphysema; Quality Control; Risk; Surface; T-Cell Activation; Technology; Transmembrane Domain; Transplant Recipients; Viral Proteins; Virus; design; human disease; latent infection; mortality; multicatalytic endopeptidase complex; mutant; pressure; prevent; research study

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.

人巨细胞病毒(HCMV)是一种可建立持续性和潜伏性感染的3-疱疹病毒。 人巨细胞病毒可导致移植受者等免疫受损个体的发病率和死亡率。 和艾滋病毒感染者。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。人巨细胞病毒也是 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障碍 智力迟缓。免疫系统对病毒的选择性压力导致了它们产生 规避策略，以避免免疫检测。巨细胞病毒表达的蛋白质同时调节先天和 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CD8+细胞毒性T细胞(CTL)的激活。人巨细胞病毒编码的基因产物 基因组独特的短区US2、US3、US6和US11干扰CTL识别HCMV- 通过阻止主要组织相容性复合体(MHC)I类分子的表面表达来感染细胞 分子。这一策略将在早期限制针对HCMV表位的CTL的频率。 人巨细胞病毒感染阶段，并允许巨细胞病毒逃脱免疫检测。US2和US11目标类别I 蛋白酶体降解的分子。最近的证据表明，US2也可能针对MHC类别 II蛋白酶体降解的DRA和DMA分子。这表明US2是一个重要的基因。 巨细胞病毒是调节免疫系统的病毒蛋白的总称。为此，我们将定义具体的 US2的区域负责靶向MHC I类分子进行破坏以及识别细胞 促进降解过程的蛋白质。我们将模拟人巨细胞病毒感染的早期阶段和 确定US2在其他病毒基因产物如US3和US11中的功能。一个完整的 了解HCMV US2如何操纵宿主的细胞机械来预防MHC I类和 II类抗原呈递可能允许设计阻断US2功能的药物。