Interferon stimulated exonuclease gene 20 kDa links psychiatric events to distinct hepatitis C virus responses in human immunodeficiency virus positive patients

Abstract

Hepatitis C Virus (HCV) infection occurs frequently in patients with preexisting mental illness. Treatment for chronic hepatitis C using interferon formulations often increases risk for neuropsychiatric symptoms. Pegylated-Interferon-α (PegIFN-α) remains crucial for attaining sustained virologic response (SVR); however, PegIFN-α based treatment is associated with psychiatric adverse effects, which require dose reduction and/or interruption. This study's main objective was to identify genes induced by PegIFN-α and expressed in the central nervous system and immune system, which could mediate the development of psychiatric toxicity in association with antiviral outcome. Using peripheral blood mononuclear cells from Human Immunodeficiency Virus (HIV)/HCV co-infected donors (N=28), DNA microarray analysis was performed and 21 differentially regulated genes were identified in patients with psychiatric toxicity vs. those without. Using these 21 expression profiles a two-way-ANOVA was performed to select genes based on antiviral outcome and occurrence of neuropsychiatric adverse events. Microarray analysis demonstrated that Interferon-stimulated-exonuclease-gene 20kDa (ISG20) and Interferon-alpha-inducible-protein 27 (IFI27) were the most regulated genes (P<0.05) between three groups that were built by combining antiviral outcome and neuropsychiatric toxicity. Validation by bDNA assay confirmed that ISG20 expression levels were significantly associated with these outcomes (P<0.035). Baseline levels and induction of ISG20 correlated independently with no occurrence of psychiatric adverse events and non-response to therapy (P<0.001). Among the 21 genes that were associated with psychiatric adverse events and 20 Interferon-inducible genes (IFIGs) used as controls, only ISG20 expression was able to link PegIFN-α related neuropsychiatric toxicity to distinct HCV-responses in patients co-infected with HIV and HCV in vivo.

Differential Specificity of Interferon-alpha Inducible Gene Expression in Association with Human Immunodeficiency Virus and Hepatitis C Virus Levels and Declines in vivo

“…Furthermore, a significant association between SVR and ISG20 induction in vivo has been described here and elsewhere [21]; however, this study was unable to detect the same association between any IFIG expression/induction and HIV-VL drop. Hence, it is conceivable that PegIFNα induces a distinct antiviral response that specifically targets HCV, which leads to clearance of HCV.…”

“…Given that IFIG expression was measured only at day_0 and week_48 in the HIV/HCV co-infected cohort (in contrast to measurements in HIV mono-infected patients that were performed at day_0 and week_3, _6, _12 and _18) our means to associate IFIG induction (ΔIFIG) with the primary endpoint of virologic response (=elimination of HCV) were confined to checking for significant associations between IFIG induction from day_0 [21] to week_48 and SVR (=HCV-VL below limit of detection at week 72). Here, induction of Interferon stimulated exonuclease gene 20 kDa (ΔISG20) showed a significant association (P<0.05) with SVR (using 1-way-ANOVA and after accounting for False Discovery Rate, FDR).…”

Comparative transcriptome analysis of PBMC from HIV patients pre- and post-antiretroviral therapy

“…This can also be confirmed by the compare H1, H2 (control group) 16 vs P1, P2, P3 (patient group) before HARRT. We find 175 DEGs ( …”

Stimulation of Interferon-Stimulated Gene 20 by Thyroid Hormone Enhances Angiogenesis in Liver Cancer

“…Recent studies have demonstrated that ISG20 is an interferon (IFN)-induced gene product with M r 20,000 [29] . ISG20 is a member of the 3′ to 5′ exonuclease family that specifically degrades single-stranded RNA [30] and, to a lesser extent, DNA, suggesting that ISG20 is a mediator of the innate immune response and potentially involved in the antiviral function of IFN against RNA viruses [14] , [29] . Moreover, IFN exerts antitumor activity against various human malignancies and appears to suppress angiogenesis through preventing endothelial cell differentiation, and not direct antiproliferative effects.…”