부산대학교 도서관

Type I interferons (IFN-Is) are a group of potent inflammatory and antiviral cytokines. They induce IFN stimulated genes (ISGs), which act as proinflammatory mediators, antiviral effectors, and negative regulators of the IFN-I signaling cascade itself. One such regulator is interferon stimulated gene 15 (ISG15). Humans with complete ISG15 deficiency express persistently elevated levels of ISGs, and consequently, exhibit broad spectrum resistance to viral infection. Here, we demonstrate that IFN-I primed fibroblasts derived from ISG15-deficient individuals are more resistant to infection with single-cycle HIV-1 compared to healthy control fibroblasts. Complementation with both wild-type (WT) ISG15 and ISG15ΔGG (incapable of ISGylation while retaining negative regulation activity) was sufficient to reverse this phenotype, restoring susceptibility to infection to levels comparable to WT cells. Furthermore, CRISPR-edited ISG15ko primary CD4+ T cells were less susceptible to HIV-1 infection compared to cells treated with non-targeting controls. Transcriptome analysis of these CRISPR-edited ISG15ko primary CD4+ T cells recapitulated the ISG signatures of ISG15 deficient patients. Taken together, we document that the increased broad-spectrum viral resistance in ISG15-deficiency also extends to HIV-1 and is driven by a combination of T-cell-specific ISGs, with both known and unknown functions, predicted to target HIV-1 replication at multiple steps. Author summary: Type I interferons (IFN-Is) are a group of potent inflammatory and antiviral agents. They induce IFN stimulated genes (ISGs), which perform downstream functions to resolve viral infection, mediate the inflammatory response, as well as negatively regulate the IFN-I signaling cascade to prevent hyperinflammation. One such negative regulator is interferon stimulated gene 15 (ISG15). Humans that lack ISG15 have chronic, low levels of antiviral ISGs, and ensuing broad-spectrum resistance to viral infection. We demonstrate that IFN-I priming of ISG15-deficient cells leads to superior resistance to human immunodeficiency virus 1 (HIV-1) infection compared to IFN-I primed healthy control cells. This is true for fibroblast cell lines, as well as primary CD4+ T cells, the main target of HIV-1. Analysis of the gene expression profiles show that ISG15-knockout CD4+ T cells express similar inflammatory markers as ISG15-deficient patients. Overall, we show that the broad-spectrum viral resistance in ISG15-deficiency extends to HIV-1. [ABSTRACT FROM AUTHOR]