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(申请人提供)：大多数逆转录病毒感染导致无限期的病毒持续，抗病毒免疫反应无法检测或低效。免疫反应性差使得阐明保护性抗逆转录病毒途径变得异常艰巨。然而，很少有人能够产生有效的抗逆转录病毒免疫反应，对这些人的研究使得对保护性反应的剖析成为可能。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大的抗病毒反应。尽管人类对逆转录病毒耐药性的研究因遗传多样性而变得复杂，但近亲交配的小鼠提供了一种实验上容易驯服的替代方案。 定位哺乳动物的抗性和易感基因。这类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)反应成功地抑制了逆转录病毒。虽然在B6小鼠中控制小鼠白血病病毒(MuLV)的基因(APOBEC3)已经被确定，但在I/LnJ小鼠中潜在的逆转录病毒抗性基因仍然未知。我们先前在I/LnJ小鼠中描述了一个病毒感染性控制基因1(Vic1)，它包含一个隐性逆转录病毒抗性相关基因，并将其定位在17号染色体上。与APOBEC3不同，vic1对两种不同的逆转录病毒，即小鼠乳房肿瘤病毒(MMTV)和小鼠乳腺肿瘤病毒(MMTV)具有抗性。尽管在易感的小鼠中观察到了最初的多种多样的抗病毒免疫反应，但这种反应是短暂的 而且不会像在耐药的ILN/J小鼠中那样转换为IgG2a反应。与对病毒敏感的小鼠不同，感染其中任何一种逆转录病毒的I/LnJ小鼠都会产生病毒中和抗体，并在一生中保持这种反应，并通过将分泌的病毒粒子包被抗病毒抗体来防止后代感染。利用同源基因和细菌人工染色体(BAC)转基因方法，我们将vic1基因定位在34,211,575-34,244,528kb之间的32.9kb区域。定位于该区域的非经典主要组织相容性II(MHCII)基因H2-Ob(Ob)通过已知的功能、独特的多态性和表型挽救实验，被鉴定为Vic1的编码基因。由H2-M催化MHCII分子在抗原提呈细胞(APC)内小体中的载肽。进化保守的Ob编码Oβ分子，与Oα一起组成异二聚体H2-O分子。H2-O是一种MHCII模拟物，并与H2-M结合，从而抑制MHCII肽的呈递。H_2-O抑制MHCII多肽负荷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完全没有被探索过。本申请中描述的目的的成功完成将揭示类MHC分子H2-O控制对逆转录病毒的免疫反应的机制。