Mechanisms of Viral Persistence

病毒持续存在的机制

• 批准号: 9207122
• 负责人: DAVID G BROOKS
• 金额: $ 27万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207122
• 关键词: Antibodies; Antiviral Agents; Automobile Driving; Biology; Cells; Chronic; Data; Disease; Functional disorder; Goals; Grant; Health; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Immune system; Immunity; Immunocompetence; Immunologic Factors; Immunosuppression; Immunosuppressive Agents; Infection; Infection Control; Inflammasome; Interferon Type I; Interferon Type II; Interferons; Interleukin-10; Journals; Legal patent; Link; Lymphocytic choriomeningitis virus; Manuscripts; Mediating; Mediator of activation protein; Medicine; Pathway interactions; Patients; Peer Review; Prevention; Production; Publishing; Regulation; Research Personnel; Role; SIV; Signal Transduction; Source; System; T-Cell Depletion; Testing; Therapeutic; Up-Regulation; Viral; Virus; Virus Diseases; Virus Replication; antiviral immunity; cell type; design; experimental study; fighting; in vivo; insight; molecular recognition; novel; pathogen; programs; public health relevance; purge; receptor; therapeutic target

 DESCRIPTION (provided by applicant): Persistent viral infections are among the greatest health concerns worldwide. By definition, immune escape is required for viral persistence, and many of the suppressive factors involved are being identified. Yet, it is still unclear how prolonged virus replication leads to the expression of the many and mechanistically diverse suppressive factors, pathways and cells that inhibit immunity during persistent viral infections. Type I interferons (IFN-I) are well known for their antiviral activity during virus infection. However, using the lymphocytic choriomeningitis virus (LCMV) system, we discovered that in addition to their critical antiviral role throughout viral persistence, sustained IFN-I production ed to many of the suppressive mechanisms and immune dysfunctions associated with persistent viral infections. Antibody blockade of IFN-I signaling decreased immunosuppression, restored immune competence and facilitated immune mediated control of the persistent infection. In the current proposal, we will mechanistically define how IFN-I functions as the mediator of the multiple and diverse parameters of immunosuppression that ultimately potentiate viral persistence. We will then test the hypothesis that the distinct antiviral and suppressive aspects of IFN-I signaling can be uncoupled to specifically inhibit the negative while maintaining the critical positive functions of IFN-I to restore immunity and control infection. These studies will provide critical biologic insight into how IFN-I simultaneously induces antiviral and suppressive functions and will potentially guide the way we therapeutically target IFN-I to treat disease. Finally, we will investigate a novel IFN-I induced mechanism of immunosuppression to define how IFN-I implements secondary down-stream effectors to promote viral persistence. Ultimately, our study will provide fundamental insight into a new aspect of IFN-I biology and facilitate the first understanding of a newly described mechanism of immunosuppression potentiating viral persistence.

 描述（由申请人提供）：持续性病毒感染是全球最大的健康问题之一，根据定义，病毒持续存在需要免疫逃逸，并且许多涉及的抑制因素正在被识别，然而，目前尚不清楚病毒复制的时间有多长。导致在持续性病毒感染期间抑制免疫的许多机械上多样化的抑制因子、途径和细胞的表达，I 型干扰素 (IFN-I) 因其在病毒感染期间的抗病毒活性而闻名。在脉络膜脑膜炎病毒 (LCMV) 系统中，我们发现，除了在病毒持续存在期间发挥关键的抗病毒作用外，持续的 IFN-I 产生还会导致与持续性病毒感染相关的许多抑制机制和免疫功能障碍。免疫抑制、恢复免疫能力并促进免疫介导的持续感染控制在当前的提案中，我们将机械地定义 IFN-I 如何作为免疫抑制的多种参数的介质发挥作用。然后，我们将测试这样的假设：IFN-I 信号传导的独特抗病毒和抑制方面可以被解耦，以特异性抑制阴性，同时保持 IFN-I 恢复免疫力和控制感染的关键积极功能。研究将为 IFN-I 如何同时诱导抗病毒和抑制功能提供重要的生物学见解，并有可能指导我们靶向 IFN-I 治疗疾病的方式。最后，我们将研究一种新的 IFN-I 诱导的免疫抑制机制。最终，我们的研究将为 IFN-I 生物学的新方面提供基本见解，并有助于首次了解新描述的增强病毒持久性的免疫抑制机制。