Down-regulation of MHC class l molecules by HCMV US2

HCMV US2 下调 MHC I 类分子

• 批准号: 7333257
• 负责人: Domenico Tortorella
• 金额: $ 38.11万
• 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/7333257
• 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

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.

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种β-疱疹病毒，可以建立持续性和潜伏性感染。 HCMV 可导致免疫功能低下的个体（例如移植受者和 HIV 感染者）发病和死亡。事实上，HIV 阳性患者面临 HCMV 相关失明的风险。 HCMV 也是新生儿出生缺陷的主要感染原因，导致听力障碍和轻度智力低下。免疫系统对病毒的选择性压力导致它们能够产生逃避策略以避免免疫检测。 HCMV 表达调节免疫系统先天性和适应性分支的蛋白质。细胞免疫似乎是 HCMV 的主要目标，重点是干扰 CD8+ 细胞毒性 T 细胞 (CTL) 的激活。 HCMV 编码的基因产物来自基因组 US2、US3、US6 和 US11 的独特短区域，通过阻止主要组织相容性复合体 (MHC) I 类分子的表面表达，干扰 HCMV 感染细胞的 CTL 识别。该策略将限制在 HCMV 感染早期阶段针对 HCMV 表位的 CTL 的频率，并允许 HCMV 逃避免疫检测。 US2 和 US11 以 I 类分子为目标进行蛋白酶体降解。最近的证据表明，US2 还可能针对 MHC II 类 DRα 和 DMα 分子进行蛋白酶体降解。这表明 US2 是 HCMV 病毒蛋白库中调节免疫系统的重要基因。为此，我们将定义 US2 的特定区域，负责靶向 MHC I 类分子进行破坏，并确定促进降解过程的细胞蛋白。我们将模拟 HCMV 感染的早期阶段，并确定 US2 在其他病毒基因产物（例如 US3 和 US11）的背景下的功能。充分了解 HCMV US2 如何操纵宿主的细胞机制来阻止 MHC I 类和 II 类抗原呈递，可能有助于设计阻断 US2 功能的药物。