Inhibitory Pathways Underlying Viral Persistance in vivo

描述（由申请人提供）：全球有超过5亿人患有慢性病毒感染。在持续性病毒感染中，T细胞功能的丧失已被注意到很长时间，但其潜在因素尚未完全了解。通过在小鼠体内感染慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV），我们最近发现TGF？在体内，CD4和CD8 T细胞上的信号可以产生强大的功能性T细胞反应。值得注意的是，病毒被迅速消灭，记忆T细胞出现。这些发现具有重要的治疗意义，因为减少TGF？信号是深刻的。然而，了解TGF？在病毒持续期间，操纵这一途径以最小的副作用增强抗病毒防御是必不可少的。在本提案中，我们计划剖析TGF？慢性病毒感染的生物学背景。我们将检查负责TGF？以及调节TGF？激活，这是暴露这种分子生物活性形式的必要步骤。我们还将确定TGF？CD4和CD8 T细胞及其与先前描述的其他抑制途径的联系。最后，我们将评估TGF？体内抑制以根除早期或完全建立的持续性感染。我们最近的发现确定了TGF？作为一种新的抑制分子负责T细胞衰竭和病毒在体内的持久性。这些观察结果为设计新的免疫疗法提供了有希望的新机会，值得进一步研究，以利用这一途径的最大潜力，在不引起免疫病理的情况下治愈或减轻人类慢性病毒疾病。公共卫生相关性：引起慢性感染的病毒，包括人类免疫缺陷病毒（HIV）、乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV），感染了全世界5亿多人，是一个主要的健康问题。通过多种保守的抑制途径，进展到慢性期与T细胞功能丧失（即耗竭）有关，这些途径似乎在不同宿主的不同慢性病毒感染中是共享的。该提案的重点是研究一种新的抑制途径，负责病毒在体内的持久性，它与其他已知的免疫抑制途径的背景联系，以及它在根除慢性病毒感染方面的治疗潜力。

DESCRIPTION (provided by applicant): Chronic viral infections afflict more than 500 million people worldwide. Loss of T cell function has been noticed for long time during persistent viral infections but the underlying factors are not completely understood. By using in vivo chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we recently found that specific and exclusive attenuation of TGF? signaling on CD4 and CD8 T cells allows the generation of a powerful and functional T cell response in vivo. Remarkably, elimination of the virus is rapidly achieved and memory T cells emerge. These findings are significant and therapeutically relevant since the effects of reducing TGF? signaling are profound. However, understanding the cellular and molecular factors underlying the role of TGF? during viral persistence is essential for manipulating this pathway to boost anti-viral defense with minimal side effects. In this proposal, we plan to dissect TGF? biology in the context of a chronic viral infection. We will examine the cell source responsible for TGF? production as well as the factors regulating TGF? activation, a required step to expose the bioactive form of this molecule. We will also determine the direct and indirect effects of TGF? on CD4 and CD8 T cells and their link to other inhibitory pathways previously described. Finally, we will evaluate the potential of TGF? inhibition in vivo to eradicate an early-stage or fully established persistent infection. Our recent findings identify TGF? as a novel inhibitory molecule responsible for T cell exhaustion and viral persistence in vivo. These observations yield promising novel opportunities to be considered for devising new immunotherapies and deserve further study to harness the greatest potential of this pathway to cure or alleviate human chronic viral diseases without causing immunopathology. PUBLIC HEALTH RELEVANCE: Viruses that cause chronic infections, including Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV), infect more than 500 million people worldwide and represent a major health problem. Progression to chronic phase has been associated with loss of T cell function (i.e. exhaustion) through multiple and conserved inhibitory pathways that appear to be shared between distinct chronic viral infections in different hosts. This proposal is focused on the study of a novel inhibitory pathway responsible for viral persistence in vivo, its contextual linkage with other known immunosuppressive pathways and its therapeutic potential for eradicating a chronic viral infection.