Targeting an immune kinase to purge KSHV latent infection

靶向免疫激酶清除 KSHV 潜伏感染

基本信息

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
项目类别：
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&apos 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

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&apos 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

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项目摘要

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.

描述（由适用提供）：人类疱疹病毒是最普遍存在的病原体，所有疱疹病毒的标志是能够在能力能力的宿主中建立终身持久感染的能力。人类γ疱疹病毒，包括Kaposi的肉瘤相关疱疹病毒（KSHV）和Epstein-Barr病毒（EBV），能够在免疫功能强化的个体中诱导肿瘤形成，包括艾滋病患者和器官移植者。实际上，开发定义艾滋病恶性肿瘤的风险，尤其是卡波西肉瘤（KSHV）和非霍奇金淋巴瘤（EBV）的风险与免疫缺陷水平高度相关。这些观察结果支持以下观点：自适应免疫组织化学对于控制KSHV和EBV的持续感染至关重要。因此，促进抗病毒免疫组织化学应大大最大程度地减少与疱疹病毒感染相关的恶性肿瘤的潜力。我们最近发现，KSHV DE从头感染潜在地激活免疫激素酶，以促进KSHV潜在感染。激酶在T细胞中也高度表达，并用作T细胞激活的负调节剂。在T细胞中，免疫因子酶的激活与TCR连接或钙影响诱导的T细胞激活偶联。这就是我们建议剖析一种用于激活激酶激活的新分子机制，并用小分子抑制剂使免疫因子酶失活，以增强抗病毒T细胞免疫学和清除持续的KSHV感染。我们的工作将建立一种通过双重作用机制消除机会性病原体的新策略：灭活KSHV感染中固有的亲载体作用并激活外部T细胞抗病毒免疫学。