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.

项目摘要 开发有效的HIV-1疫苗仍然是一个尚未实现的目标。在这一奋进中取得成功 需要更好地了解HIV-1如何与适应性免疫系统结合， 包括CD 4 + T细胞（TCD 4+），它们有助于有效的体液免疫和免疫调节的发展。 细胞免疫TCD 4+被与主要抗原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 肽来源于细胞外抗原，其被降解并加载到新生的MHC上， II在抗原呈递细胞（APC）的内体区室中。然而，我们的工作与 流感病毒和鼠痘病毒表明肽的产生要复杂得多， 几种基本上不同的抗原处理模式在起作用。之间分工 这些模式由诸如病毒体的物理性质和复制等参数控制 策略，这是每种病毒所独有的。这种分化对HIV-1的影响尚不清楚，因为 令人惊讶的是，尽管这一领域的工作有可能产生重大影响， 合理的疫苗设计在这里，我们建议阐明MHC-II加工景观， HIV-1，并开始调查潜在的加工机制。R21融资 机制将作为一个跳板，继续在一个方向的机制研究， 另一方面，将新兴概念应用于合理的疫苗设计。