Immunologic and Metabolic Profiles of T cells that control diverse HCV infections

控制多种 HCV 感染的 T 细胞的免疫学和代谢特征

• 批准号: 10398150
• 负责人: ANDREA L COX
• 金额: $ 81.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10398150
• 关键词: Acute; Antibody Response; Antigens; Assessment tool; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Chronic Hepatitis C; Data; Development; Disease Outcome; Failure; Flow Cytometry; General Hospitals; Generations; Genetic Transcription; Genotype; Goals; Gold; Hepatitis C; Hepatitis C Vaccine; Hepatitis C virus; Human; Immune; Immune response; Immunity; Immunologics; Infection; Infection Control; Libraries; Massachusetts; Measures; Mediating; Memory; Metabolic; Mus; Outcome; Pan Genus; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Placebos; Population; Primary Infection; Property; RNA; Recovery; Regimen; Risk; Role; Specimen; T cell receptor repertoire sequencing; T cell response; T memory cell; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Universities; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; acute infection; base; chronic infection; cohort; efficacy trial; healthy volunteer; high dimensionality; high risk; immunogenicity; memory CD4 T lymphocyte; metabolic abnormality assessment; metabolic profile; nonhuman primate; novel; patient population; prevent; programs; prophylactic; response; single-cell RNA sequencing; vaccine candidate; vaccine response; vaccine strategy

HCV Vaccine Program Project 1 Summary Evidence from chimpanzee and human studies support critical roles for CD4 and CD8 T lymphocyte responses in the control HCV infection, yet defining the correlates of protective HCV immunity has been challenging. Identifying CD4 and CD8 T cell memory that protects against infection from multiple different HCV genotypes and subtypes is a cornerstone in prophylactic HCV vaccine design. Our groups at Johns Hopkins University and Massachusetts General Hospital have contributed many key findings to the current understanding of HCV- specific T cell immunity, based on the combination of large and well documented patient cohorts with robust and sensitive experimental tools for the assessment of both CD8 and CD4 responses targeting HCV. We will build on this expertise and employ newly developed approaches to study the metabolism and transcriptional landscape of HCV-specific CD4 and CD8 T cells in order to assess T cell immunity in unique patient cohorts. We previously demonstrated that clearance occurs more often in reinfection than in primary infection, with reduced peak and duration of viremia associated with broadened T cell responses vs. initial infection of the same person. This suggests induction of memory that protects against infection from multiple different HCV genotypes and subtypes - a central goal of prophylactic HCV vaccine design. Using a population of patients who have cleared as many as six distinct HCV infections, we plan to better define the specific correlates of T cell mediated protection from chronic HCV infection. In addition, we will leverage access to research specimens from the only prophylactic HCV vaccine regiment tested in an at-risk human population. This regimen, consisting of a ChAd3NS prime followed by an MVA-NS boost, did not protect against chronic infection, but did induce T cells specific for vaccine NS antigens and suppressed geometric mean peak HCV RNA vs. placebo recipients. Specimens from this trial provide a unique opportunity to study the effect of vaccine- induced T cells on incident HCV infection, allowing us to further validate T cell properties associated with control of HCV, but also to identify the reasons for failure of this potent T cell based vaccine. Specifically, we propose: Aim 1: To define the critical characteristics of HCV-specific CD8 T-cell responses in spontaneous recovery from repeated HCV infection as determinants of protective immunity. Aim 2 To determine if specific CD8 T cell characteristics are associated with vaccine induced suppression of peak viremia in subsequent HCV infection. Aim 3: To define effective CD4 T cell responses in acute infection and HCV-specific CD4 memory T cells in patients with multiple episodes of successfully controlled HCV infection. Aim 4: To characterize the HCV-specific CD4 memory T cell population post vaccination and its response after HCV exposure. We build on our combined extensive expertise in studying both CD8 and CD4 T cell responses in order to define the effector and memory T cell responses that control diverse HCV infections, defining goals for T cell induction in HCV vaccines to be tested in Projects 3 (non-human primates) and 5 (mice) and, ultimately, in humans.

HCV疫苗计划项目1总结 来自黑猩猩和人类研究的证据支持CD 4和CD 8 T淋巴细胞应答的关键作用 在控制HCV感染方面，然而确定保护性HCV免疫的相关性一直是具有挑战性的。 鉴定保护免受多种不同HCV基因型感染的CD 4和CD 8 T细胞记忆 和亚型是预防性HCV疫苗设计的基石。我们在约翰霍普金斯大学和 马萨诸塞州总医院为目前对HCV的理解提供了许多关键发现- 特异性T细胞免疫，基于大型和有据可查的患者队列的组合， 敏感的实验工具，用于评估针对HCV的CD 8和CD 4应答。 我们将建立在这方面的专业知识，并采用新开发的方法来研究代谢， HCV特异性CD 4和CD 8 T细胞的转录景观，以评估T细胞免疫， 患者队列。我们以前证明，清除发生更经常在再感染比原发性 与初始感染相比， 感染同一个人。这表明记忆的诱导可以保护免受多种病毒的感染， 不同的HCV基因型和亚型-预防性HCV疫苗设计的中心目标。使用群体 在已经清除了多达六种不同HCV感染的患者中，我们计划更好地定义特定的 相关的T细胞介导的保护慢性HCV感染。此外，我们还将利用 来自在高危人群中测试的唯一预防性HCV疫苗方案的研究标本。 该方案由ChAd 3 NS初免和随后的MVA-NS加强组成，不能防止慢性病毒感染。 感染，但确实诱导了对疫苗NS抗原特异性的T细胞，并抑制了HCV的几何平均峰值 RNA与安慰剂接受者。这项试验的样本提供了一个独特的机会来研究疫苗的效果- 诱导的T细胞对HCV感染事件，使我们能够进一步验证T细胞特性与控制相关 的HCV，但也要确定这种有效的T细胞为基础的疫苗失败的原因。具体而言，我们建议： 目的1：确定HCV特异性CD 8 T细胞应答在HCV感染后自发恢复中的关键特征。 反复感染HCV是保护性免疫的决定因素。目的2确定特异性CD 8 T细胞是否 这些特征与随后HCV感染中疫苗诱导的峰值病毒血症抑制相关。 目的3：确定急性感染中有效的CD 4 T细胞应答和HCV特异性CD 4记忆T细胞， 多次成功控制HCV感染的患者。目的4：表征HCV特异性 接种疫苗后的CD 4记忆T细胞群及其在HCV暴露后的应答 我们建立在我们在研究CD 8和CD 4 T细胞应答方面的广泛专业知识的基础上， 控制不同HCV感染的效应和记忆T细胞应答，定义T细胞诱导的目标 在项目3（非人类灵长类动物）和项目5（小鼠）中进行测试，并最终在人类中进行测试。