Defining the MHC-II processing and presentation landscape of HIV-1

定义 HIV-1 的 MHC-II 处理和表达景观

• 批准号: 9762836
• 负责人: Laurence Crane Eisenlohr
• 金额: $ 21.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762836
• 关键词: Adaptive Immune System; Antibodies; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Area; Attention; B-Lymphocytes; Biology; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Chemicals; Complex; Cross Presentation; Dendritic Cells; Development; Ectromelia; Engineering; Epitopes; Funding Mechanisms; Generations; Goals; HIV; HIV vaccine; HIV-1; HIV-1 vaccine; HLA-DR1 Antigen; Histocompatibility Antigens Class II; Humoral Immunities; Individual; Infection; Infectious Ectromelia; Influenza; Investigation; Knock-out; Link; MHC antigen; Measures; Mediating; Modeling; Mouse Pox Virus; Outcome; Pathway interactions; Peptides; Play; Poxviridae; Predisposition; Process; Property; Proteins; Role; Small Interfering RNA; System; T Virus; Testing; Therapeutic; Type II Epithelial Receptor Cell; Vaccine Design; Vaccines; Viral; Virion; Virus; Virus Diseases; Work; antigen processing; direct application; extracellular; flu; influenzavirus; knock-down; macrophage; nonhuman primate; novel; physical property; protein B; response; success; symposium; vaccine candidate; vaccine trial; vpu Protein

Project Summary Development of an effective HIV-1 vaccine remains an unmet goal. Success in this endeavor will require a better understanding of how HIV-1 engages the adaptive immune system, including CD4+ T cells (TCD4+) that are instrumental in the development of effective humoral and cellular immunity. TCD4+ are activated by antigen-derived peptides complexed with Major Histocompatibility Complex class II molecules (MHC-II). According to convention, these peptides are derived from extracellular antigen that is degraded and loaded onto nascent MHC- II in the endosomal compartment of an antigen presenting cell (APC). However, our work with influenza and ectromelia viruses indicates that peptide generation is far more complex, with several fundamentally distinct antigen processing modes in play. Division of labor between these modes is governed by parameters such as physical properties of the virion and replication strategy, which is unique to each virus. How this division plays out for HIV-1 is unknown, since surprisingly little work has been done in this area despite the potential for major impact on rational vaccine design. Here we propose to elucidate the MHC-II processing landscape for HIV-1, and initiate investigation of the underlying processing machinery. This R21 funding mechanism will serve as a springboard for continued mechanistic studies in one direction, and the application of emerging concepts to rational vaccine design in the other.

项目概要 开发有效的 HIV-1 疫苗仍然是一个未实现的目标。这次努力的成功 需要更好地了解 HIV-1 如何参与适应性免疫系统， 包括 CD4+ T 细胞 (TCD4+)，它们有助于开发有效的体液和 细胞免疫。 TCD4+ 被与主要成分复合的抗原衍生肽激活 组织相容性复合物 II 类分子 (MHC-II)。按照惯例，这些 肽源自细胞外抗原，该抗原被降解并加载到新生的 MHC- II 位于抗原呈递细胞 (APC) 的内体区室中。然而，我们的工作与 流感病毒和节肢动物病毒表明肽的生成要复杂得多， 几种根本不同的抗原处理模式在发挥作用。之间的分工 这些模式由病毒粒子的物理特性和复制等参数控制 策略，每种病毒都是独一无二的。这种分裂对于 HIV-1 的作用尚不清楚，因为 令人惊讶的是，尽管这方面可能会产生重大影响，但在这一领域所做的工作却很少。 合理的疫苗设计。在这里，我们建议阐明 MHC-II 处理景观 HIV-1，并启动对底层加工机械的调查。此次 R21 资助 该机制将作为一个跳板，继续朝一个方向进行机械研究，并且 另一方面，新兴概念在合理疫苗设计中的应用。