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（由申请方提供）：大多数逆转录病毒感染导致病毒无限期持续存在，抗病毒免疫应答不可检测或无效。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令人难以置信的艰巨奋进。然而，很少有个体能够产生有效的抗逆转录病毒免疫应答，对这些个体的研究已经允许解剖保护性应答。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和维持强有力的抗病毒应答。鉴于人类逆转录病毒耐药性的研究因遗传多样性而复杂化，近交系小鼠提供了一种实验上易于处理的替代方案， 绘制哺乳动物的抗性和易感基因。这种模型的两个实例是来自C57 BL/6 J（B6）和I/LnJ品系的小鼠，其通过产生中和抗体（Ab）应答成功地抑制逆转录病毒。尽管已经鉴定了B6小鼠中负责控制鼠白血病病毒（MuLV）的基因（apobec 3），但I/LnJ小鼠中逆转录病毒耐药性的潜在基因仍然未知。我们以前描述了一个病毒感染性控制器1（vic 1）位点，含有一个隐性逆转录病毒耐药基因，并将其定位于染色体17。与apobec 3不同，vic 1对两种不同的逆转录病毒MuLV和小鼠乳腺肿瘤病毒（MMTV）具有抗性。虽然在易感小鼠中观察到初始的多同种型抗病毒免疫应答，但该应答是短暂的。 并且不像在抗性ILn/J小鼠中那样向IgG 2a应答类别转换。与病毒易感小鼠不同，感染任一逆转录病毒的I/LnJ小鼠产生病毒中和抗体，在其整个生命中维持这种应答，并通过用抗病毒抗体包被分泌的病毒体来防止后代感染。利用同源基因和细菌人工染色体（BAC）转基因方法，我们将vic 1基因座精细定位到34，211，575 - 34，244，528 Kbs之间的32.9Kb区域。一个非经典的主要组织相容性II类（MHCII）基因，H2-Ob（Ob）映射的区域内被确定为基因编码的Vic 1凭借其已知的功能，独特的多态性和表型拯救实验。抗原呈递细胞（APC）的内体中MHCII分子的肽负载由H2-M催化。进化上保守的Ob编码Oβ分子，O β分子与Oα一起构成异源二聚体H2-O分子。H2-O是MHCII模拟物并结合H2-M，从而抑制MHCII肽呈递。H2-O抑制MHCII肽负载的生物学相关性知之甚少。重要的是，H2-O在针对任何病原体的免疫应答期间的作用完全未被探索。本申请中描述的目标的成功完成将揭示MHC样分子H2-O控制对逆转录病毒的免疫应答的机制。