Basic—Liver, Pancreas, and Biliary TractCell-Type Specific Gene Expression Signature in Liver Underlies Response to Interferon Therapy in Chronic Hepatitis C Infection
Section snippets
Chronic HCV
Seventy-eight patients with CHC (56 genotype 1, 22 genotype non-1) were treated at University Health Network from October 2001 through May 2004. All patients underwent pretreatment percutaneous liver biopsy and had baseline viral loads determined. Treatment was either PegIFN2a 180 μg or PegIFN2b 1.5 μg/kg subcutaneously weekly and oral ribavirin 800–1200 mg daily for 24 (genotypes 2/3) or 48 (genotypes 1, 4, and 6) weeks. Quantitative HCV-RNA was determined at completion of therapy and 6 months
Patient Demographics
Demographic and clinical variable data on the 78 CHC patients are summarized in Table 1. The majority (72%) was infected with HCV genotype 1. Patients were denoted “low fibrosis” if their Ishak scores were 0–2 and “high fibrosis” if their scores were 3 or 4.27 Similarly, patients were classified “low activity” if their METAVIR A scores were 0–2 and “high activity” for scores of 3 or 4. For this study, high viral load was defined as >8 × 106 IU/mL. Comparing genotype 1 and non-1 patients, there
Discussion
Although the molecular mechanisms involved in IFN resistance in CHC patients who do not respond to treatment are not well understood, the interaction between viral and host factors plays a critical role. In this study, we present evidence that chronic infection with HCV leads to 2 different states at the level of hepatic gene and protein expression: one, the “high ISG” NR phenotype, is associated with high level ISG expression in hepatocytes; the other, the “low ISG” R phenotype, has more ISG
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2018, GeneCitation Excerpt :Unless the exact differences in the target functions of both IFN-λ3 and IFN-λ4 are understood, or a deeper understanding of the molecular mechanism is available, it is difficult to attribute a particular phenotype to one of the two mutually exclusive mechanisms. For instance, in chronic HCV patients receiving IFN-RBV therapy, the well-established phenomenon of excess stimulation of ISG expression leading to non-response to therapy by minor allele carriers (Noureddin et al., 2015; Chen et al., 2005; Sarasin-Filipowicz et al., 2008; Chen et al., 2010; Honda et al., 2010; Urban et al., 2010; Dill et al., 2011; Onomoto et al., 2011), allows us to implicate IFN-λ4 and not IFN-λ3 as causal; such a mechanistic understanding is usually lacking in other cases in order to implicate either IFN-λ3 or IFN-λ4 as being causal. Therefore, due to the mutual exclusivity of the two scenarios (Fig. 4) and overlapping functions of IFN-λ3 and IFN-λ4 (Fig. 3; Lauber et al., 2015), the exact causal nature cannot be established with certainty given the limitations of in vivo research in humans.
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2016, Journal of Biological ChemistryCitation Excerpt :Although ISGs, cytokines, and chemokines are highly induced in HCV-infected liver (1, 2), the innate immune responses alone are unable to contain the virus (30). Paradoxically, high basal expression of ISGs as a result of activation of the endogenous IFN system is the strongest factor that predicts poor response to IFN-based therapy in CHC patients (31–33). In light of this, the precise role of GRP78 in innate immune responses to HCV in vivo will require further study.
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Conflicts of interest The authors disclose no conficts.
Funding Supported by grants from the Canadian Institute of Health Research (No. 62488; to I.D.M), by the National Canadian Research Training Program in Hepatitis C (NCRTP-HepC; to L.C. and I.B.), and by a Canada Graduate Scholarship (CGS) from the Canadian Institute of Health Research (to L.C.).