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New retroviral restriction factor

新的逆转录病毒限制因子

基本信息

批准号：
10441970
负责人：
Tatyana V Golovkina
金额：
$ 77.62万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-11-13 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10441970
关键词：
Address Affect Affinity Alleles Amino Acid Substitution Amino Acids Animals Antibody Response Antigen Presentation Antigen Presentation Pathway Antigens Antiviral Agents B-Lymphocytes BALB/cJ Mouse Binding Biochemical Bioinformatics Cellular biology Chronic Control Animal Data Development Family Generations Genes Genetic Genetic Crosses Hepatitis B Hepatitis C Herpesviridae Histocompatibility Histocompatibility Antigens Class II Homologous Gene Human I/LnJ Mouse Immune response Immunoglobulin Domain Infection Knock-in Knowledge Leptin Link Lymphomagenesis Malignant Neoplasms Measures Mediating Mouse Mammary Tumor Virus Murine leukemia virus Mus Mutation Outcome Pathogenesis Peptides Phenotype Process Production Protocols documentation Recessive Genes Regulation Resistance Retroviridae Rodent Testing Vaccination Vaccines Variant Viral Viral Pathogenesis Virus Virus Diseases adaptive immune response gain of function improved loss of function mutant neutralizing antibody novel pathogen positional cloning protein function prototype response tool

项目摘要

Abstract Select humans and animals are able to control persistent viral infections via adaptive immune responses that include the development of neutralizing antibodies (Abs). However, the mechanisms underlying these exceptional protective responses remain largely unknown. Using positional cloning approach, we have identified a gene responsible for virus-neutralizing Ab responses in mice from the I/LnJ strain following infection with two distinct retroviruses, Mouse Mammary Tumor Virus (MMTV) and Murine Leukemia Virus (MuLV). This gene is H2-Ob (Ob), which encodes the b subunit (H2-Ob) of the ab obligate heterodimer H2-O. H2-O (DO in humans), is a non-classical Major Histocompatibility Class II (MHCII)-like molecule and a known negative regulator of the MHCII antigen presentation pathway. The recessive loss-of-function I/LnJ Ob allele allowed for the production of potently neutralizing Abs in infected mice. Subsequent bioinformatics and functional analyses of the human homologues - DOa and DOb - revealed both loss- and gain-of-function variants, several of which were genetically linked to the differential outcomes of hepatitis B and C viral infections in humans. The process of loading of MHCII molecules with peptides is mediated by the interaction of MHCII with another non-polymorphic MHCII-like molecule, H2-M (HLA-DM in humans), which loads MHCII molecules with high-affinity, pathogen-derived peptides. H2-M function is opposed by H2-O, which acts as an MHCII mimic, binding to H2-M and blocking its ability to catalyze MHCII peptide loading. Importantly, our studies showed that this accepted paradigm of a direct competition between H2-O/DO and MHCII for binding to H2-M/DM was incomplete, because I/LnJ Ob, as well as some human DOa and DOb variants result in H2-O/DO molecules, which fail to inhibit peptide loading of MHCII and yet retain the ability to interact with H2-M/DM. Clearly, there are severe gaps in our knowledge of how H2-O/DO negatively regulates MHCII presentation, a central process directing effective immune responses. The studies in this renewal application seek to address these gaps. Specifically, Aim1 will elucidate the mechanism underpinning the loss of inhibition of H2-M function by the mutant H2-O found in I/LnJ mice as a means to understand how H2-O normally functions. Aim 2 seeks to discover novel genes involved in the regulation of the H2-O-dependent control of MHCII peptide loading and Aim 3 will determine how two different viruses (a retrovirus and a gherpesvirus) exploit H2-O regulation to suppress the anti-viral immune response and/or to promote viral pathogenesis.

摘要选择的人类和动物能够通过适应性免疫反应控制持续的病毒感染，包括开发中和抗体（Abs）。然而，这些潜在的机制特殊的保护性反应在很大程度上仍不为人所知。使用位置克隆方法，我们有鉴定了I/LnJ株小鼠中负责病毒中和抗体应答的基因，感染两种不同的逆转录病毒，小鼠乳腺肿瘤病毒（MMTV）和小鼠白血病病毒（MuLV）。该基因为H2-O B（O B），其编码ab专性异源二聚体H2-O的B亚基（H2-O B）。 H2-O（人体中的DO）是一种非经典的主要组织相容性II类（MHCII）样分子，并且是已知的 MHCII抗原呈递途径的负调节因子。隐性功能丧失I/LnJ Ob等位基因允许在受感染的小鼠中产生有效的中和抗体。随后的生物信息学和对人类同源物DOa和DOb的功能分析显示，变异，其中几种与B型和C型肝炎病毒的不同结果有遗传联系。人类感染。用肽装载MHCII分子的过程由MHCII与肽的相互作用介导。另一种非多态性MHCII样分子，H2-M（人类HLA-DM），其负载MHCII分子，高亲和力的病原体衍生肽。H2-M功能与H2-O相反，H2-O充当MHCII模拟物，结合H2-M并阻断其催化MHCII肽加载的能力。重要的是，我们的研究表明， H2-O/DO和MHCII之间直接竞争结合H2-M/DM的公认范例是不完全，因为I/LnJ Ob以及一些人DOa和DOb变体导致H2-O/DO分子，其不能抑制MHCII的肽负载，但仍保留与H2-M/DM相互作用的能力。显然我们对H2-O/DO如何负调节MHCII呈递的认识存在严重差距，这是一个中心过程，引导有效的免疫反应。本次更新申请中的研究旨在解决这些差距。具体而言，Aim 1将阐明在I/LnJ小鼠中发现的突变型H2-O抑制H2-M功能丧失的基础机制，了解H2-O如何正常工作。目的2旨在发现参与基因突变的新基因。 MHCII肽负载和Aim 3的H2-O依赖性控制的调节将决定两种不同的病毒（逆转录病毒和疱疹病毒）利用H2-O调节来抑制抗病毒免疫反应和/或促进病毒发病。