Interplay between Negative Regulators of Type I Interferon and HIV control

I 型干扰素负调节因子与 HIV 控制之间的相互作用

• 批准号: 9411359
• 负责人: Dusan Bogunovic
• 金额: $ 25.43万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-10 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9411359
• 关键词: AIDS/HIV problem; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Biology; Blood; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cell Line; Cells; Code; Communicable Diseases; Complement; DNA Viruses; Data; Defense Mechanisms; Disease; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; HIV; HIV Infections; HIV-1; HIV-2; Health; Herpesvirus 1; Highly Active Antiretroviral Therapy; Human; ISG15 gene; Immune; Immunity; Individual; Infection; Infection Control; Inflammation; Interferon Type I; Interferons; Intervention; Invaded; Investigation; Knock-out; Life Cycle Stages; Molecular; Molecular Mimicry; Molecular Profiling; Mutation; Pathogenesis; Patients; Pattern; Peptide Hydrolases; Phenotype; Predisposition; Principal Investigator; Process; Proteins; RNA Viruses; Regulation; Reporter; Resistance; Rift Valley fever virus; Role; Series; Signal Transduction; Technology; Testing; Therapeutic Intervention; Ubiquitin; Variant; Viral; Virus; autoinflammation; cell type; cytokine; experimental study; genetic signature; improved; influenzavirus; mutant; nano-string; novel; pathogen; prevent; response; tool; viral resistance

PROJECT SUMMARY/ABSTRACT Humans possess multi-layered defenses against invading pathogens. One of the first antiviral defense mechanisms is the induction of Type I Interferons (IFNs). IFNs are cytokines with well-defined antiviral activities. They induce transcription of hundreds of IFN stimulated genes (ISGs). We discovered and characterized six individuals with complete ISG15 deficiency. The cells of these patients presented with mild IFN auto-inflammation and decreased susceptibility to a broad spectrum of viruses. Thus, ISG15 acts as an anti-inflammatory as well as a proviral molecule. Our studies ascribed ISG15 a role of negative regulator of IFN signaling explaining these two phenotypes. More recently we also discovered five patients with a complete USP18 deficiency, a master negative regulator of IFN signaling. This proposal is built around the hypothesis that germ line mutations in negative regulators of IFN afford increased control of HIV infection. Our preliminary data indicate that HIV is restricted in IFN primed cells from ISG15 deficient patients. We propose test if USP18 deficient individuals' cells also have increased resistance to HIV. Naturally deficient patient cell line will be complemented with a series of ISG15 and USP18 variants in order to discriminate between negative regulation and ISGylation as underlying mechanism of action. We will also determine what step in the HIV life cycle is specifically targeted in the context of ISG15/USP18 deficiency. We will also evaluate whether primary CD4+ T cells deficient in ISG15 or USP18 control HIV better compared to control cells and investigate the extent to which cells from HIV infected patients that spontaneously control infection display expression signatures of ISGs that mimic the unique expression patterns found in patients with deleterious mutations in ISG15 and USP18. These studies have the potential to radically change our understanding of naturally occuring HIV control and point to new interventions suitable to yield functional cures for HIV/AIDS disease.

项目摘要/摘要 人类对入侵的病原体具有多层次的防御能力。最早的抗病毒防御之一 机制是诱导I型干扰素(IFN)。干扰素是一种细胞因子，具有明确的抗病毒作用 活动。它们诱导数百个干扰素刺激基因(ISGs)的转录。我们发现并 具有6个完全缺乏ISG15的个体的特征。这些患者的细胞表现出轻微的 干扰素自发性炎症，降低对广谱病毒的易感性。因此，ISG15充当 抗炎和前病毒分子。我们的研究认为ISG15是一种负调控因子 干扰素信号可以解释这两种表型。最近，我们还发现五名患者患有 完全性USP18缺乏症，干扰素信号的主要负调节因子。 这一建议是建立在这样一个假设之上的，即干扰素的负调控因子中的生殖系突变 加强对艾滋病毒感染的控制。我们的初步数据表明，HIV在干扰素诱导的细胞中受到限制 ISG15缺乏者。我们建议测试USP18缺陷个体的细胞是否也增加了抵抗力 为艾滋病毒干杯。天然缺陷的患者细胞系将被一系列ISG15和USP18变异体补充 以便区分负调控和ISG化作为潜在的作用机制。我们会 还应确定在ISG15/USP18缺乏的情况下，艾滋病毒生命周期中的哪个步骤是专门针对的。 我们还将评估与ISG15和USP18缺陷的原始CD4+T细胞相比，哪个控制HIV的效果更好 控制细胞并调查HIV感染患者的细胞自发控制的程度 感染显示ISGs的表达特征，模仿在患者中发现的独特表达模式 具有ISG15和USP18的有害突变。这些研究有可能从根本上改变我们的 了解自然发生的艾滋病毒控制，并指出适合产生功能性治疗的新干预措施 用于艾滋病毒/艾滋病。