New retroviral restriction factor

新的逆转录病毒限制因子

• 批准号: 9029814
• 负责人: Tatyana V Golovkina
• 金额: $ 65.98万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-13 至 2020-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029814
• 关键词: Alleles; Anti-Retroviral Agents; Antibody Response; Antigen-Presenting Cells; Antiviral Response; Bacterial Artificial Chromosomes; Binding; Biological; CD4 Positive T Lymphocytes; Chromosomes, Human, Pair 17; Complex; Data; Dissection; Down-Regulation; Endosomes; Genes; Genetic; Genetic Polymorphism; Genetic Variation; HIV; HIV-1; Health; Histocompatibility; Human; I/LnJ Mouse; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Inbred C57BL Mice; Inbred Mouse; Individual; Infection; Infection prevention; Knowledge; Lead; Life; MHC Class II Genes; Maps; Mediating; Missense Mutation; Molecular; Mouse Mammary Tumor Virus; Murine leukemia virus; Mus; Mutate; Mutation; Outcome; Pathway interactions; Peptides; Phenotype; Production; Proteins; Protocols documentation; Regulation; Research Design; Resistance; Retroviridae; Role; Structure; Susceptibility/Resistance Gene; Transgenic Organisms; Vaccination; Viral; Virion; Virus; base; congenic; improved; loss of function; mouse model; neutralizing antibody; pathogen; protein function; research study; response

 DESCRIPTION (provided by applicant): Most retroviral infections result in indefinite viral persistence with an undetectable or inefficient anti-virus immune response. Poor immune reactivity has made the elucidation of protective anti-retroviral pathways an incredibly arduous endeavor. There are, however, rare individuals capable of mounting a potent anti-retroviral immune response, and the study of these individuals has allowed dissection of the protective responses. For example, some Human Immunodeficiency Virus (HIV)-infected individuals termed `long-term or elite non-progressors' are able to initiate and maintain robust anti-viral responses via specific genetic mechanisms. Whereas studies of retrovirus resistance in humans are complicated by genetic diversity, inbred mice offer an experimentally tractable alternative for mapping mammalian resistance and susceptibility genes. Two examples of such models are mice from the C57BL/6J (B6) and I/LnJ strains, which successfully constrain retroviruses via production of neutralizing antibody (Ab) responses. Whereas the gene responsible for controlling Murine Leukemia Virus (MuLV) in B6 mice has been identified (apobec3), the gene underlying retrovirus resistance in I/LnJ mice remains unknown. We have previously described a virus infectivity controller 1 (vic1) locus, containing a recessive retrovirus resistance-conferrng gene in I/LnJ mice and mapped it to Chromosome 17. Unlike apobec3, vic1 confers resistance to two distinct retroviruses, MuLV and Mouse Mammary Tumor Virus (MMTV). Although an initial poly-isotypic anti-virus immune response is observed in susceptible mice, it is short-lived and does not class-switch to an IgG2a response as it does in resistant ILn/J mice. Unlike virus-susceptible mice, I/LnJ mice infected with either retrovirus produce virus-neutralizing Abs, sustain this response throughout their life, and prevent infection of progeny by coating secreted virions with anti-virus Abs. Using congenic and bacterial artificial chromosome (BAC) transgenic approaches, we fine- mapped the vic1 locus to a 32.9Kb region between 34,211,575 -34,244,528 Kbs. A non-classical major histocompatibility class II (MHCII) gene, H2-Ob (Ob) mapped within the region was identified as the gene encoding for Vic1 by virtue of its known function, unique polymorphism and a phenotype rescue experiment. Peptide loading of MHCII molecules in the endosomes of antigen presenting cells (APCs) is catalyzed by H2-M. The evolutionally conserved Ob encodes the Oβ molecule that together with Oα, comprises the heterodimeric H2-O molecule. H2-O is a MHCII mimic and binds to H2-M thereby inhibiting MHCII peptide presentation. The biological relevance of H2-O inhibition of MHCII peptide loading is poorly understood. Importantly, the role of H2-O during the immune response against any pathogen is completely unexplored. The successful completion of aims described in this application will reveal the mechanism by which the MHC-like molecule, H2-O controls the immune response to retroviruses.

 描述（由申请人提供）：大多数逆转录病毒感染会导致无限期的病毒持续存在，并伴有不可检测或低效的抗病毒免疫反应。免疫反应性差使得阐明保护性抗逆转录病毒途径成为一项极其艰巨的工作。然而，很少有个体能够产生有效的抗逆转录病毒免疫反应，对这些个体的研究已经允许对保护性反应进行剖析。例如，一些被称为“长期或精英非进展者”的人类免疫缺陷病毒（HIV）感染者能够通过特定的遗传机制启动并维持强大的抗病毒反应。尽管人类逆转录病毒抗性的研究由于遗传多样性而变得复杂，但近交小鼠提供了一种实验上易于处理的替代品 绘制哺乳动物抗性和易感性基因图谱。这种模型的两个例子是来自 C57BL/6J (B6) 和 I/LnJ 品系的小鼠，它们通过产生中和抗体 (Ab) 反应成功地限制了逆转录病毒。虽然 B6 小鼠中负责控制鼠白血病病毒 (MuLV) 的基因已被鉴定 (apobec3)，但 I/LnJ 小鼠中潜在的逆转录病毒抗性基因仍然未知。我们之前在 I/LnJ 小鼠中描述了病毒感染性控制器 1 (vic1) 基因座，该基因座包含隐性逆转录病毒抗性基因，并将其定位到 17 号染色体。与 apobec3 不同，vic1 赋予对两种不同逆转录病毒 MuLV 和小鼠乳腺肿瘤病毒 (MMTV) 的抗性。尽管在易感小鼠中观察到最初的多同型抗病毒免疫反应，但这种反应是短暂的 并且不会像耐药 ILn/J 小鼠那样类别转换为 IgG2a 反应。与病毒易感小鼠不同，感染任一逆转录病毒的 I/LnJ 小鼠都会产生病毒中和抗体，在其一生中维持这种反应，并通过用抗病毒抗体包被分泌的病毒颗粒来防止后代感染。使用同类和细菌人工染色体 (BAC) 转基因方法，我们将 vic1 基因座精细定位到 34,211,575 -34,244,528 Kb 之间的 32.9Kb 区域。定位在该区域内的非经典主要组织相容性 II 类 (MHCII) 基因 H2-Ob (Ob) 凭借其已知的功能、独特的多态性和表型拯救实验，被鉴定为编码 Vic1 的基因。 H2-M 催化抗原呈递细胞 (APC) 内体中 MHCII 分子的肽负载。进化上保守的 Ob 编码 Oβ 分子，与 Oα 一起组成异二聚体 H2-O 分子。 H2-O 是 MHCII 模拟物，与 H2-M 结合，从而抑制 MHCII 肽呈递。 H2-O 抑制 MHCII 肽负载的生物学相关性尚不清楚。重要的是，H2-O 在针对任何病原体的免疫反应中的作用尚未完全被探索。本申请中描述的目标的成功完成将揭示 MHC 样分子 H2-O 控制逆转录病毒免疫反应的机制。