Interplay between Negative Regulators of Type I Interferon and HIV control

项目总结/摘要 人类对入侵的病原体拥有多层次的防御。最早的抗病毒防御之一 其机制是I型干扰素（IFN）的诱导。IFN是具有明确的抗病毒作用的细胞因子， 活动它们诱导数百种IFN刺激基因（ISG）的转录。我们发现， 鉴定了六个具有完全ISG 15缺陷的个体。这些患者的细胞呈现轻度 IFN自身炎症和对广谱病毒的易感性降低。因此，ISG 15作为 抗炎以及前病毒分子。我们的研究认为ISG 15是一种负调节因子， IFN信号解释了这两种表型。最近，我们还发现了五名患有 完全USP 18缺陷，IFN信号传导的主要负调节因子。 这个建议是建立在假设的基础上的，即在IFN负调节基因中的生殖系突变提供了 加强艾滋病毒感染控制。我们的初步数据表明，HIV仅限于IFN引发的细胞， ISG 15缺陷患者。我们建议测试USP 18缺陷个体的细胞是否也具有增加的抗性 艾滋病毒。天然缺陷患者细胞系将用一系列ISG 15和USP 18变体进行补充， 为了区分负调节和ISGylation作为潜在的作用机制。我们将 还确定在ISG 15/USP 18缺陷的背景下，HIV生命周期中的哪一步是专门针对的。 我们还将评估ISG 15或USP 18缺陷的原代CD 4 + T细胞是否能更好地控制HIV， 控制细胞，并研究HIV感染患者的细胞自发控制 感染显示ISG的表达特征，其模拟在患者中发现的独特表达模式 在ISG 15和USP 18中存在有害突变。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 for HIV艾滋病/AIDS艾滋病disease疾病.

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.