Novel Strategies for Controlling Persistent Viral Infection

控制持续病毒感染的新策略

• 批准号: 9248857
• 负责人: John Ross Teijaro
• 金额: $ 48.13万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248857
• 关键词: Address; Antibodies; Antibody Formation; Antibody Response; Antiviral Agents; Architecture; B-Lymphocytes; Biochemical Pathway; Biological Response Modifiers; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Chimera organism; Complement; Data; Development; Environment; Equilibrium; Future; Generations; Genetic; Goals; Grant; HIV/HCV; Helper-Inducer T-Lymphocyte; Hepatitis B; Human; Humoral Immunities; IFNAR1 gene; Immune; Immune response; Immune system; Immunosuppression; Impairment; Infection; Interferons; Interleukin-10; Interleukin-6; Knowledge; LoxP-flanked allele; Lymphocytic choriomeningitis virus; Lymphoid; Lymphoid Tissue; Mediating; Modality; Modeling; Molecular; Mus; Natural Killer Cells; Output; PDCD1LG1 gene; Partner in relationship; Plasma; Plasma Cells; Play; Public Health; Publishing; Reporting; Role; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Time; Transcriptional Activation; Translational Research; Viral; Virus; Virus Diseases; base; biochemical tools; exhaustion; in vivo; neutralizing antibody; novel strategies; prevent; public health relevance; purge; receptor; response; therapeutic development; transcription factor

 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.

 描述（由适用提供）：持续性病毒感染代表了一个重大的公共卫生问题，数亿人感染了。但是，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疗法失败了。在过去的十年中，研究表明，持续的病毒利用了负免疫调节分子（IL-10，PD-1）来抑制抗病毒CD4和CD8 T细胞反应，从而导致T细胞衰竭，从而启用病毒持久性。删除了几种免疫刺激分子，例如IL-6和IL-21导致终身病毒持久性，这表明阴性和阳性免疫调节剂之间的平衡决定了病毒清除率或持久性。重要的是，诸如IL-6和IL-21之类的分子具有卵泡辅助细胞（TFH）和B细胞刺激能力以及这些分子在体内的部署导致TFH，B细胞反应和抗体产生的降低。实际上，人类的研究表明，尽管在人类持续性病毒感染期间产生了TFH和生发中心（GC）B细胞，但其功能受损。尽管有上述发现，但在持续性病毒感染过程中限制/促进最佳TFH，B和抗体反应的机制尚不完全了解。我们最近提出了一个意外的发现，即在持续的LCMV感染过程中，IFN-I信号传导对于促进（而不是预防）病毒持久性至关重要。重要的是，IFN-I信号传导支持诱导阴性免疫调节剂（NIR）IL-10和PD-L1，免疫抑制，T细胞耗尽和淋巴组织破坏。遵循我们已发表的研究，我们现在报告说，IFN-I信号传导的封锁导致TFH，GC和血浆B细胞反应增强。我们假设IFN-I信号传导限制了持续性病毒感染期间抗病毒体液免疫性。 该提案的最终目标是产生详细的理解IFN-I信号传导如何调节持续性病毒感染期间的免疫血液。我们的研究的输出应是详细的细胞和分子理解IFN-I在持续性病毒感染过程中如何调节抗病毒体液和细胞免疫血液的调节。在该项目中，将使用抗IFNAR1中和抗体，遗传和生化工具来确定IFNAR1信号如何调节模型持续病毒感染期间TFH，GC和血浆B细胞反应。该提案涵盖了重要的基本和潜在翻译的研究目标 - 1）了解IFNAR1信号抑制免疫物功能的机制； 2）发现IFN-I调节促进病毒持久性的细胞和生化途径； 3）利用这一知识来指导未来的治疗方式发展，以促进免疫组对控制人类持续性病毒感染的反应。