Immune correlates of protection against hepacivirus persistence.

抵抗肝炎病毒持久性的免疫相关性。

• 批准号: 10594475
• 负责人: Amit Kapoor
• 金额: $ 61.48万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594475
• 关键词: Acceleration; Address; Adenovirus Vector; Adenoviruses; Adjuvant; Animal Model; Animals; Antigens; Antiviral Agents; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell surface; Cellular Immunity; Chronic; Communication; Data; Dissection; Epitope Mapping; Escape Mutant; Failure; Future; Genetic Variation; Goals; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Hepatitis C-Like Viruses; Human; Human papillomavirus 16 E1 protein; Humoral Immunities; Immune; Immunity; Immunocompetent; Individual; Infection; Knowledge; Mediating; Modeling; Mus; Nature; Nonstructural Protein; Outcome; Pan Genus; Paper; Phenotype; Play; Proteins; RNA Virus Infections; RNA vaccine; Rattus; Reporting; Rodent; Role; Stains; Structural Protein; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccinated; Vaccination; Vaccines; Variant; Viral; Virus; Virus Diseases; cell killing; chronic infection; cytokine; env Gene Products; experimental study; in vivo; innovation; insight; neutralizing antibody; novel; prevent; single-cell RNA sequencing; transcriptome; vaccination strategy; vaccine development; vaccine failure; vaccine trial; vaccine-induced immunity

Abstract Although direct acting antivirals can cure Hepatitis C virus (HCV) infection, a vaccine is necessary to stop new infections, and to prevent re-infections in the cured individuals. Studies in humans and chimpanzees suggest that both T cells and neutralizing antibodies (nAb) can play an important role in the clearance of HCV infection. However, further progress on HCV vaccine development has been stymied by a lack of animal models. Notably, the nature, breadth, and relative contribution of humoral and cellular immunity in determining the outcomes of HCV infection remain poorly understood. We recently showed that a rat hepacivirus (HCV-like virus), RHV, shares the hallmarks of HCV infection and immunity. A majority of fully-immunocompetent rats develop lifelong viral persistence, and thus rats are appropriate models for “proof-of-concept” vaccination studies to prevent HCV- like viral persistence, the desired goal of HCV vaccines. We further validated this model by determining that like reported from HCV studies in chimpanzees, rats vaccinated using an Adenovirus expressing RHV non-structural (NS) proteins develop partial protection against persistence of a homologous RHV strain (Nature communications, PMC6405742). Interestingly, we observed that the vaccinated rats that cleared a homologous virus developed more efficient and broader immunity for homologous and heterologous viruses, and T cell escape variants. These results suggest that the short- term viral infection either enhances T cell immunity or generates nAbs, or both, to confer effective immunity against heterologous viruses. Most importantly, these results are promising for defining the nature of immunity that confers effective protection against persistent infection of genetically diverse viruses, like HCV variants. The overall goal of this project is to define the immune correlates of protection against hepacivirus persistence. Specific aim-1 is to define the T cell correlates of protection against hepacivirus persistence. Our hypothesis is that the nature and breadth of virus-specific T cells determines the fate of hepacivirus infections. Specific aim-2 is to study the role of envelope proteins (E1/E2) induced immunity and importance of nAbs in virus clearance. Our hypothesis is that a vaccination approach using a combination of NS and E1E2 vaccines will increase the immunity against viral persistence. Specific Aim- 3 is to define the breadth of vaccine induced immunity, and to identify the viral determinants of vaccine failure. Our hypothesis is that vaccination can prevent persistence of genetically diverse viruses that share only a few T cell epitopes. The proposed dissection of vaccine and short-term viral infection conferred immunity is necessary to understand the relative contributions of T and B cells in hepacivirus clearance, and this knowledge can help in conceptualizing an effective vaccination strategy for HCV. Finally, the proposed characterization of T and B cell immunity in this unique model of life-long persistent RNA virus infection will pave the way for testing of newer vaccination approaches (like RNA vaccines) to prevent chronic virus infection.

抽象的 尽管直接作用抗病毒药可以治愈丙型肝炎病毒（HCV）感染，但要阻止新的疫苗需要疫苗 感染，并防止在固化个体中重新感染。人类和黑猩猩的研究表明 T细胞和中和抗体（NAB）都可以在清除HCV感染中起重要作用。 然而，缺乏动物模型所阻碍了HCV疫苗发育的进一步进展。尤其， 体液和细胞免疫在确定结果中的性质，广度和相对贡献 HCV感染的理解仍然很差。我们最近表明，大鼠肝病毒（HCV样病毒）， RHV具有HCV感染和免疫组织化学的标志。大多数完全免疫能力的大鼠发展 终身病毒持久性，因此大鼠是“概念证明”疫苗接种研究的合适模型 防止HCV持续性，这是HCV疫苗的所需目标。我们通过 像从黑猩猩的HCV研究中报道的那样，使用腺病毒疫苗接种的大鼠 表达RHV非结构性（NS）蛋白会产生局部保护，以防止持续存在 同源性RHV菌株（自然通信，PMC6405742）。有趣的是，我们观察到 清除同源病毒的疫苗接种大鼠对 同源和异源病毒，以及T细胞逃生变体。这些结果表明短暂 术语病毒感染可以增强T细胞免疫学或产生NAB，或两者兼具，以赋予有效的免疫学 反对异源病毒。最重要的是，这些结果被承诺以定义的性质 赋予有效保护的免疫力，以防止持续感染一般的多元病毒，例如HCV 变体。该项目的总体目标是定义针对肝病毒的保护剂 持久性。特定目的1是定义针对肝病毒持久性保护的T细胞相关性。 我们的假设是病毒特异性T细胞的性质和广度决定了肝病毒的命运 感染。特定目的2是研究包膜蛋白（E1/E2）的作用，诱导免疫力和重要性 病毒清除中的NAB。我们的假设是一种结合NS和 E1E2疫苗将增加对病毒持久性的免疫力。特定目标 - 3是定义宽度 疫苗诱导免疫力，并确定疫苗衰竭的病毒决定剂。我们的假设是 疫苗接种可以防止仅具有几个T细胞表位的一般多元化病毒的持久性。这 拟议的疫苗的解剖和短期病毒感染赋予免疫是必要的 T和B细胞在肝病毒间隙中的相对贡献，这些知识可以帮助 概念化HCV的有效疫苗策略。最后，提出的T和B的表征 在这种独特的终身持久性RNA病毒感染模型中，细胞免疫将为新的测试铺平道路 疫苗接种方法（如RNA疫苗）可预防慢性病毒感染。