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（由适用提供）：大多数逆转录病毒感染导致无限期的病毒持久性，具有无法检测的或无效的抗病毒免疫响应。不良的免疫反应性使对受保护的抗逆转录病毒途径的阐明变得非常艰巨。但是，有罕见的个体能够安装潜在的抗逆转录病毒免疫响应，并且对这些个体的研究允许解剖受保护的反应。例如，某些人类免疫缺陷病毒（HIV）感染的个体被称为“长期或精英非培训者”，能够通过特定的遗传机制启动和维持强大的抗病毒反应。尽管人类逆转录病毒抗性的研究使遗传多样性变得复杂，而近近交生小鼠为实验可牵引的替代方案提供了可用于实验的替代方案 映射哺乳动物的抗性和敏感性基因。此类模型的两个例子是来自C57BL/6J（B6）和I/LNJ菌株的小鼠，它们通过产生中和抗体（AB）反应成功地限制了逆转录病毒。尽管已经鉴定出负责控制B6小鼠中鼠白血病病毒（MULV）的基因（APOBEC3），但I/LNJ小鼠中逆转录病毒抗性的基因仍然未知。我们先前已经描述了病毒感染控制器1（VIC1）基因座，其中包含I/LNJ小鼠中隐性逆转录病毒抗性 - 抗性基因，并将其映射到17号染色​​体上。与apobec3不同，VIC1与两个不同的逆转录病毒（Mulv and Mulv and Mimalm amamm amamm amammary tumormary tumor tumor tumor virus）（MMMMALMARMARY TUMOR VIRUS（MMMMMMTV）都赋予了抗性。尽管在易感小鼠中观察到了初始的多型抗病毒免疫响应，但它是短暂的 并且不像在耐药性ILN/J小鼠中那样向IgG2A反应进行类别开关。与病毒敏感的小鼠不同，感染任何一种逆转录病毒的I/LNJ小鼠会产生病毒中和ABS，在整个生命中维持这种反应，并通过抗病毒ABS涂层涂层的分泌病毒来防止进展感染。使用先天和细菌性人造染色体（BAC）转基因方法，我们将VIC1基因座贴上了32.9kb区域，在34,211,575 -34,244,528 kbs之间。映射在该区域内的非古典主要组织相容性II类（MHCII）基因，H2-OB（OB）被鉴定为vic1编码的基因，该基因凭借其已知功能，独特的多态性和表型救援实验。 H2-M催化抗原呈递细胞内体（APC）中MHCII分子的肽负荷。循环构成的OB编码Oβ分子与Oα一起包含异二聚体H2-O分子。 H2-O是MHCII模拟物，与H2-M结合，从而抑制MHCII肽的表现。 H2-O抑制MHCII肽负荷的生物学相关性知之甚少。重要的是，H2-O在免疫反应中针对任何病原体的作用是完全出乎意料的。在本应用中描述的目标的成功完成将揭示MHC样分子H2-O控制对逆转录病毒的免疫响应的机制。