Novel Strategies for Controlling Persistent Viral Infection

 描述(申请人提供)：持续的病毒感染是一个重大的公共卫生问题，有数亿人感染。然而，由于对促进病毒持久性的细胞和分子机制的了解有限，使宿主能够清除这些感染的治疗方法一直不成功。过去十年的研究表明，持久性病毒利用负性免疫调节分子(IL-10、PD-1)抑制抗病毒的CD4和CD8 T细胞反应，导致T细胞耗尽，使病毒持续存在。几种免疫刺激分子如IL-6和IL-21的缺失会导致病毒的终生持续，这表明正负免疫调节因子之间的平衡决定了病毒的清除或持续。重要的是，IL-6和IL-21等分子具有已知的T滤泡辅助细胞(TFH)和B细胞刺激能力，体内这些分子的耗尽会导致TFH、B细胞反应和抗体产生的减少。事实上，对人类的研究表明，尽管在人类持续病毒感染期间会产生TFH和生发中心(GC)B细胞，但它们的功能受到了损害。尽管有上述发现，但在持续病毒感染期间抑制/促进最佳TFH、B和抗体反应的机制尚不完全清楚。我们最近有了一个意想不到的发现，在LCMV持续感染期间，干扰素-I信号对于促进(而不是防止)病毒持续是必不可少的。重要的是，干扰素-I信号支持负免疫调节因子(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，我们现在报告，阻断干扰素-I信号会导致TFH、GC和血浆B细胞反应增强。因此，我们假设在持续病毒感染期间，干扰素-I信号抑制了抗病毒体液免疫。 这项建议的最终目标是详细了解干扰素-I信号如何在持续病毒感染期间调节免疫反应。我们研究的成果应该是详细的细胞和分子理解干扰素-I如何在持续病毒感染期间调节抗病毒体液和细胞免疫反应。在这个项目中，将使用抗IFNAR1中和抗体、遗传和生化工具来确定IFNAR1信号如何在模型持续病毒感染期间调节TFH、GC和血浆B细胞反应。这项建议包括重要的基础和潜在的转译研究目标-1)了解IFNAR1信号抑制免疫细胞功能的机制；2)发现干扰素-I调节的促进病毒持久性的细胞和生化途径；以及3)利用这一知识指导未来治疗方法的发展，以促进免疫反应，以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.