Targeting an immune kinase to purge KSHV latent infection

靶向免疫激酶清除 KSHV 潜伏感染

• 批准号: 9116597
• 负责人: Pinghui Feng
• 金额: $ 67.66万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9116597
• 关键词: Acquired Immunodeficiency Syndrome; Affinity Chromatography; Anatomy; Antiviral Agents; Antiviral Therapy; Calcium; Cells; Complex; Coupled; Epithelial Cells; Glutamine; Herpesviridae; Herpesviridae Infections; Homologous Gene; Human; Human Herpesvirus 4; Human Herpesvirus 8; Immune; Immune Targeting; Immune response; Immunity; Individual; Infection; Interferons; Invaded; Kaposi Sarcoma; Knock-out; Lead; Life; Ligase; Ligation; Lymphoma; Malignant Neoplasms; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Hodgkin' s Lymphoma; Oncogenic; Oral; Oral cavity; Oral mucous membrane structure; Organ Transplantation; Pathogenesis; Patients; Phosphorylation; Phosphotransferases; Primary Infection; Production; Property; Protein Kinase; Protein-Serine-Threonine Kinases; Proteins; Recruitment Activity; Regulation; Reporting; Risk; Role; Signal Transduction; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Transplant Recipients; Viral; Virus; Virus Diseases; Work; adaptive immunity; antiviral immunity; combat; deamidation; design; gammaherpesvirus; inhibitor/antagonist; insight; latent infection; latent persistent infection; mortality; mouse model; novel; pathogen; prevent; public health relevance; purge; small hairpin RNA; small molecule inhibitor; small molecule libraries; tumor; virus host interaction

 DESCRIPTION (provided by applicant): Human herpesviruses are the most ubiquitous pathogens and a hallmark of all herpesviruses is the ability to establish life-long persistent infection in an immune-competent host. Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are capable of inducing tumor formation in immune-compromised individual, including AIDS patients and organ transplant recipients. In fact, the risk of developing AIDS-defining malignancies, especially Kaposi's sarcoma (KSHV) and non-Hodgkin's lymphoma (EBV), is highly associated with the level of immune-deficiency. These observations support the notion that adaptive immunity is crucial to control the persistent infection of KSHV and EBV. Consequently, boosting antiviral immunity should greatly minimize the potential to malignancies associated with herpesvirus infection. We have recently discovered that KSHV de novo infection potently activates an immune kinase to facilitate KSHV latent infection. The kinase is also highly expressed in T cells and functions as a negative regulator of T cell activation. In T cells, the activation of the immun kinase is coupled to T cell activation induced by TCR ligation or calcium influx. Thus, we propose to dissect a new molecular mechanism governing kinase activation and to inactivate the immune kinase with small-molecule inhibitors to boost antiviral T cell immunity and purge persistent KSHV infection. Our work will establish a new strategy to eliminate opportunistic pathogens via dual mechanisms of action: inactivating the intrinsic pro-latent role in KSHV infection and activating the extrinsic T cell antiviral immunity.

 性状（由申请方提供）：人疱疹病毒是最普遍存在的病原体，所有疱疹病毒的特征是能够在免疫活性宿主中建立终身持续感染。人类γ疱疹病毒，包括卡波西肉瘤相关疱疹病毒（Kaposi's sarcoma-associated herpesvirus，KSHV）和爱泼斯坦-巴尔病毒（Epstein-Barr virus，EBV），能够在免疫受损个体（包括艾滋病患者和器官移植受者）中诱导肿瘤形成。事实上，发展艾滋病定义的恶性肿瘤，特别是卡波西肉瘤（KSHV）和非霍奇金淋巴瘤（EBV）的风险与免疫缺陷水平高度相关。这些观察结果支持了适应性免疫对于控制KSHV和EBV的持续感染至关重要的观点。因此，加强抗病毒免疫应大大减少与疱疹病毒感染相关的恶性肿瘤的可能性。我们最近发现，KSHV从头感染有效地激活免疫激酶，以促进KSHV潜伏感染。该激酶也在T细胞中高度表达，并作为T细胞活化的负调节剂发挥作用。在T细胞中，免疫激酶的活化与由TCR连接或钙内流诱导的T细胞活化偶联。因此，我们建议剖析一个新的分子机制，管理激酶激活和免疫激酶与小分子抑制剂，以提高抗病毒T细胞免疫和清除持续KSHV感染。我们的工作将建立一个新的战略，以消除机会病原体通过双重作用机制：灭活内在的前潜伏作用KSHV感染和激活外源性T细胞抗病毒免疫。