Mechanisms of Viral Persistence

病毒持续存在的机制

基本信息

批准号：
7766095
负责人：
DAVID G BROOKS
金额：
$ 38万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Persistent viral infections are a worldwide health concern, with over 500 million people infected with HIV and hepatitis B and C viruses (HBV, HCV). By definition, immune escape is required for viral persistence; however the suppressive mechanisms that abort immunity during persistent viral infections are not well defined. T cell responses are crucial to prevent and control viral infections. Although robust T cell responses are initially mounted to these viruses, T cells rapidly lose activity permitting persistence. Recent evidence suggests that the functionally non-responsive T cell state (exhaustion) is not programmed during T cell activation, but that T cell responses are actively suppressed throughout infection. We discovered that infection with a persistent strain of lymphocytic choriomeningitis virus (LCMV) triggers high IL-10 production that directly ablates T cell function and causes viral persistence. Antibody blockade of IL-10 restored T cell activity and purged the persistent infection, indicating that host regulatory mechanisms actually permit viral persistence and are actively responsible for preventing clearance. This research suggests the exciting prospect that, when freed, T cells are capable of controlling persistent viruses. A better understanding of how immunosuppressive factors inhibit immunity is critical for the design of therapies to re-establish immune control and prevent and potentially eradicate persistent viral infections. In the current proposal I will define the mechanisms leading to IL-10 mediated immunosuppression during persistent viral infection. I will utilize cutting- edge microscopy techniques to directly visualize immunosuppressive cells in vivo and the specific interactions that suppress T cell function and sustain T cell exhaustion. These studies will provide the first in vivo mechanistic insights into how host molecules cause immunosuppression during persistent viral infection. I will then test a novel strategy to enhance T cell immunity and purge a long- lived reservoir of viral replication from an immune privileged site. Once completed this effort will have a direct impact toward our understanding of host-virus interactions, the mechanisms employed to promote viral clearance versus persistence and therapeutically the ability to restore immune function to completely eliminate persistent infection. PUBLIC HEALTH RELEVANCE: Strategies to enhance immune activity to clear persistent viral infections have so far been unsuccessful because it is unclear what is required of the immune response to purge virus once it proceeds past acute infection. The experiments outlined in this proposal will investigate a novel factor required to clear a persistent viral infection. Identification of the mechanisms that sustain immunity will aid in the design of therapies to amplify the immune response to control persistent viral infections

描述（由申请人提供）：持续性病毒感染是一个全球性的健康问题，超过 5 亿人感染了 HIV 以及乙型和丙型肝炎病毒（HBV、HCV）。根据定义，免疫逃逸是病毒持续存在所必需的。然而，在持续性病毒感染期间中止免疫力的抑制机制尚不明确。 T 细胞反应对于预防和控制病毒感染至关重要。尽管最初对这些病毒产生了强大的 T 细胞反应，但 T 细胞很快失去了允许持续存在的活性。最近的证据表明，功能上无反应的 T 细胞状态（衰竭）在 T 细胞激活过程中并未被编程，但 T 细胞反应在整个感染过程中受到积极抑制。我们发现，淋巴细胞性脉络膜脑膜炎病毒 (LCMV) 持久性菌株的感染会引发高 IL-10 产生，直接削弱 T 细胞功能并导致病毒持续存在。 IL-10 抗体阻断可恢复 T 细胞活性并清除持续感染，表明宿主调节机制实际上允许病毒持续存在，并积极负责防止清除。这项研究提出了一个令人兴奋的前景：T 细胞在释放后能够控制持久性病毒。更好地了解免疫抑制因素如何抑制免疫力对于设计重建免疫控制、预防和潜在根除持续性病毒感染的疗法至关重要。在当前的提案中，我将定义在持续病毒感染期间导致 IL-10 介导的免疫抑制的机制。我将利用尖端显微镜技术直接观察体内免疫抑制细胞以及抑制 T 细胞功能和维持 T 细胞耗竭的特定相互作用。这些研究将为宿主分子在持续病毒感染期间如何引起免疫抑制提供第一个体内机制见解。然后我将测试一种新策略，以增强 T 细胞免疫力并从免疫特权位点清除长期存在的病毒复制库。一旦完成，这项工作将对我们对宿主病毒相互作用、促进病毒清除与持久性的机制以及恢复免疫功能以完全消除持续性感染的治疗能力的理解产生直接影响。公共卫生相关性：迄今为止，增强免疫活性以清除持续性病毒感染的策略尚未成功，因为尚不清楚一旦病毒经过急性感染，免疫反应需要什么来清除病毒。该提案中概述的实验将研究清除持续病毒感染所需的新因素。识别维持免疫力的机制将有助于设计放大免疫反应以控制持续性病毒感染的疗法