Novel Strategies for Controlling Persistent Viral Infection

 描述（由申请人提供）：持续性病毒感染是一个重大的公共卫生问题，有数亿人感染。然而，由于对促进病毒持续存在的细胞和分子机制的理解有限，使宿主能够清除这些感染的疗法一直不成功。在过去的十年中，研究表明，持久性病毒利用负性免疫调节分子（IL-10，PD-1）来抑制抗病毒CD 4和CD 8 T细胞应答，导致T细胞耗竭，使病毒持久存在。几种免疫刺激分子如IL-6和IL- 21的缺失导致终身病毒持续存在，表明阴性和阳性免疫调节剂之间的平衡决定了病毒清除或持续存在。重要的是，诸如IL-6和IL-21的分子具有已知的T滤泡辅助细胞（TFH）和B细胞刺激能力，并且这些分子在体内的消耗导致TFH、B细胞应答和抗体产生减少。事实上，对人体的研究已经证明，尽管TFH和生发中心（GC）B细胞在人类持续性病毒感染期间产生，但它们的功能受损。尽管有上述发现，但在持续性病毒感染期间抑制/促进最佳TFH、B和抗体应答的机制尚未完全了解。 我们最近取得了意想不到的发现，在持续LCMV感染期间，IFN-I信号传导对促进（而不是预防）病毒持续存在至关重要。重要的是，IFN-I信号传导支持负性免疫调节因子（NIR）IL-10和PD-L1的诱导、免疫抑制、T细胞耗竭和淋巴组织破坏。根据我们已发表的研究，我们现在报道，阻断IFN-1信号传导导致增强的TFH、GC和血浆B细胞应答。因此，我们假设IFN-I信号抑制抗病毒的体液免疫在持续的病毒感染。 该提案的最终目标是详细了解IFN-I信号传导如何在持续病毒感染期间调节免疫反应。我们的研究结果应该是一个详细的细胞和分子理解IFN-Ⅰ如何调节抗病毒的体液和细胞免疫反应在持续的病毒感染。在这个项目中，将使用抗IFNAR 1中和抗体，遗传和生化工具，以确定如何IFNAR 1信号调节TFH，GC和血浆B细胞反应在模型持续病毒感染。该提案包括重要的基础和潜在的转化研究目标- 1）了解IFNAR 1信号转导抑制免疫细胞功能的机制; 2）发现IFN-I调节的促进病毒持续存在的细胞和生化途径; 3）利用这些知识指导未来开发治疗方式，以促进免疫反应，控制人类持续性病毒感染。

 DESCRIPTION (provided by applicant): Persistent viral infections represent a significant public health problem with hundreds of millions of people infected. However, therapies that enable the host to purge these infections have been unsuccessful due to a limited understanding of the cellular and molecular mechanisms that promote virus persistence. Over the last decade studies have demonstrated that persistent viruses take advantage of negative immune regulatory molecules (IL-10, PD-1) to suppress the antiviral CD4 and CD8 T cell responses, resulting in T cell exhaustion, enabling virus persistence. Deletion of several immune stimulatory molecules such as IL-6 and IL- 21 result in lifelong virus persistence, suggest that the balance between negative and positive immune regulators determines virus clearance or persistence. Importantly, molecules such as IL-6 and IL-21 have known T follicular helper cell (TFH) and B cell stimulatory capacities and depletion of these molecules in vivo results in reduced TFH, B cell responses and antibody production. In fact, studies in humans have demonstrated that although TFH and germinal center (GC) B cells are generated during human persistent virus infection, their function is impaired. Despite the above findings, the mechanisms that restrain/promote optimal TFH, B and antibody responses during persistent virus infection are incompletely understood. We recently made the unexpected finding that during persistent LCMV infection IFN-I signaling was essential to promoting (rather than preventing) virus persistence. Importantly, IFN-I signaling supported induction of negative immune regulators (NIR) IL-10 and PD-L1, immune suppression, T cell exhaustion and lymphoid tissue destruction. Following up our published studies we now report that blockade of IFN-I signaling results in enhanced TFH, GC and plasma B cell responses. Thus we hypothesize IFN-I signaling restrains antiviral humoral immunity during persistent virus infection. The ultimate goal of this proposal is to generate a detailed understanding how IFN-I signaling modulates immune responses during persistent virus infection. The output of our studies should be a detailed cellular and molecular understanding how IFN-I regulates anti-viral humoral and cellular immune responses during persistent virus infection. In this project will use anti-IFNAR1 neutralizing antibodies, genetic and biochemical tools to determine how IFNAR1 signaling regulates TFH, GC and plasma B cell responses during a model persistent virus infection. This proposal encompasses important basic and potentially translational research goals - 1) to understand the mechanisms by which IFNAR1 signaling suppresses immune cell function; 2) discover IFN-I regulated cellular and biochemical pathways that promote virus persistence; and 3) leverage this knowledge to instruct future development of therapeutic modalities to promote immune responses to control of human persistent viral infection.