Interplay between Negative Regulators of Type I Interferon and HIV control

点击翻译按钮获取中文摘要

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.