Inhibitory Pathways Underlying Viral Persistance in vivo

描述(申请人提供)：慢性病毒感染困扰着全球超过5亿人。在持续的病毒感染过程中，T细胞功能的丧失已经被注意到很长一段时间，但潜在的因素还不完全清楚。通过在小鼠体内感染慢性淋巴细胞性脉络膜脑膜炎病毒(LCMV)，我们最近发现，转化生长因子？CD4和CD8T细胞上的信号允许在体内产生强大的、有功能的T细胞反应。值得注意的是，病毒很快就被清除了，记忆性T细胞出现了。这些发现具有重要的治疗意义，因为降低转化生长因子的效果？信号是深刻的。然而，了解转化生长因子作用的细胞和分子因素？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。在这项建议中，我们计划解剖转化生长因子？在慢性病毒感染的背景下的生物学。我们会检查转化生长因子的细胞来源吗？生产以及调节转化生长因子的因素？激活，这是暴露这种分子的生物活性形式所必需的步骤。我们还将确定转化生长因子的直接和间接影响？对CD4和CD8T细胞及其与前面描述的其他抑制通路的联系。最后，我们将评估转化生长因子？的潜力。体内抑制，以根除早期或完全确定的持续性感染。我们最近的发现确定了转化生长因子？作为一种新的抑制分子，与体内T细胞耗竭和病毒持续存在有关。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缓解人类慢性病毒疾病。公共卫生相关性：导致慢性感染的病毒，包括人类免疫缺陷病毒(HIV)、乙肝病毒(乙肝病毒)和丙型肝炎病毒(丙型肝炎病毒)，感染着全球5亿多人，是一个主要的健康问题。进展到慢性期与T细胞功能丧失(即衰竭)有关，通过多个保守的抑制途径，这些途径似乎在不同宿主的不同慢性病毒感染之间共享。这项建议侧重于研究一种导致病毒在体内持续存在的新的抑制途径，它与其他已知的免疫抑制途径的联系，以及它根除慢性病毒感染的治疗潜力。

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.