Influence of Genes Suppressing Interferon Effects in Peripheral Blood Mononuclear Cells during Triple Antiviral Therapy for Chronic Hepatitis C

Abstract

The levels of expression of interferon-stimulated genes (ISGs) in liver are associated with response to treatment with pegylated interferon (PEG-IFN) plus ribavirin (RBV). However, associations between the responses of ISGs to IFN-based therapy and treatment efficacy or interleukin-28B (IL28B) genotype have not yet been determined. Therefore, we investigated the early responses of ISGs and interferon-lambdas (IFN-λs) in peripheral blood mononuclear cells (PBMCs) during PEG-IFN/RBV plus NS3/4 protease inhibitor (PI) therapy. We prospectively enrolled 50 chronic hepatitis C patients with HCV genotype 1, and collected PBMCs at baseline, 8 and 24 h after the initial administration of PEG-IFN/RBV/PI. Levels of mRNAs for selected ISGs and IFN-λs were evaluated by real-time PCR. All 31 patients with a favorable IL28B genotype and 13 of 19 with an unfavorable genotype achieved sustained virological responses (SVR). Levels of mRNA for A20, SOCS1, and SOCS3, known to suppress antiviral activity by interfering with the IFN signaling pathway, as well as IRF1 were significantly higher at 8 h in patients with an unfavorable IL28B genotype than in those with a favorable one (P = 0.007, 0.026, 0.0004, 0.0006, respectively), especially in the non-SVR group. Particularly, the fold-change of IRF1 at 8 h relative to baseline was significantly higher in non-SVR than in SVR cases with an unfavorable IL28B genotype (P = 0.035). In conclusion, levels of several mRNAs of genes suppressing antiviral activity in PBMCs during PEG-IFN/RBV/PI differed according to IL28B genotypes, paralleling treatment efficacy.

Suppressor of cytokine signaling 1 expression in peripheral blood mononuclear cells of hepatitis C genotype 1 patients

“…17,20,21 These results are consistent with our initial finding that SOCS1 expression is upregulated in SVR patients compared with non-SVR patients based on a multiplex RT-PCR analysis. However, SOCS-1 expression did not differ between SVR and non-SVR patients in the large sample of 100 patients.…”

Association between IL28B rs12979860 single nucleotide polymorphism and the frequency of colonic Treg in chronically HCV-infected patients

“…This significant relationship was verified using a univariate regression model for IL28B genotypes on colonic T reg cells. A recent report suggested that the TT genotype is associated with an increase in IL28B induction upon IFN stimulation and lower levels of several mRNAs of genes [43]. Some of those genes, such as SOCS1, SOCS3, and IRF1, are associated with T reg induction and maintenance [44–46].…”

Hepatic IFNL4 expression is associated with non‐response to interferon‐based therapy through the regulation of basal interferon‐stimulated gene expression in chronic hepatitis C patients

“…Based on recent studies, the mRNA levels of the following ISGs were quantified by real‐time PCR in 45 of 49 patients: ISG15 ubiquitin‐like modifier ( ISG15 ), ubiquitin specific peptidase 18 ( USP18 ), MX dynamin‐like GTPase 1 ( MX1 ), and retinoic acid‐inducible gene 1 ( RIG ‐ I , encoded by DDX58), ubiquitin ligase ring‐finger protein 125 ( RNF125 ), suppressor of cytokine signaling 1 ( SOCS1 ), suppressor of cytokine signaling 3 ( SOCS3 ), and ring finger protein 11 ( RNF11 ). The specific primers and probes for ISG15 , MX1 , RIG‐I , SOCS1 , SOCS3 , RNF125 , and the specific primers for USP18 were described in the previous reports, and the specific primers and probes for RNF11 were obtained from Applied Biosystems (Carlsbad, CA) as TaqMan Gene Expression Assays (RNF11: Hs00702517_s1). Amplification and detection were performed using an ABI PRISM 7900HT Fast Real‐Time PCR System (Applied Biosystems).…”