The Induction of Type I Interferon Production in Hepatitis C–Infected Patients

Abstract

Chronic infection with hepatitis C virus (HCV) is a major global health problem. One way HCV may evade the host immune response is by inhibiting the production of type I interferon (IFN). In addition, the standard treatment for chronic HCV infection involves treatment with IFN-alpha (or its pegylated derivative), alone or in combination with ribavirin. Therefore, it is believed that an important reason that most HCV-infected individuals progress from acute to chronic infection is due to a defect in the host response. In this study, we examined the host response to HCV infection in a cohort of patients enrolled in the UTHSC Cooperative HCV Research Center by determining levels of biologically active IFN in the sera of patients. We found that 15 of 35 enrolled HCV-infected patients show serum levels of IFN (ranging from 2 to 40 IU/mL) before initiation of therapy. Uninfected individuals do not have circulating levels of IFN. Basal IFN levels do not correlate with the clinical response to therapy, nor do they reflect the age, sex, or race of patients. These results suggest that the differential response of patients most likely reflects a defect in the later stages of the host innate immune response, such as the cellular response to endogenous or exogenous IFN. In contrast, the early stage of the host immune response in vivo of many HCV-infected patients (approximately 40%) is intact as determined by IFN production.

Targeted impairment of innate antiviral responses in the liver of chronic hepatitis C patients

“…Consequently, expressed ISGs can originate from the detectable, but low level of IL28A produced during early antiviral phase mediated by CARDIF or from extrahepatic sources of IFN (e.g., infiltrated immune cells) that act in a paracrine manner through the Jak-STAT signal transduction pathway. IFN levels are indeed detected in serum of 43% of chronically HCV-infected patients suggesting that some patients are able to trigger an initial immune response consistent with the intrahepatic ISGs upregulation observed in this study and described previously [31]. Moreover, experiments using paired liver biopsies and PBMCs collected from HCV-infected patients demonstrated upregulated ISGs -but not IFN genes -in liver biopsies [32,33] in contrast to induction of both ISGs and various type I IFN subtypes in circulating PBMCs.…”

Altered interferon-α-signaling in natural killer cells from patients with chronic hepatitis C virus infection

“…Both IFN-a and IFN-c have been observed in sera from patients with CHC [21,22]. Their production may be induced by a host response to HCV within the liver, which would make these IFNs detectable in the systemic circulation of patients with CHC.…”

Differential alteration of CD56bright and CD56dim natural killer cells in frequency, phenotype, and cytokine response in chronic hepatitis C virus infection

“…We have recently shown that NK cells from patients with CHC display a higher level of STAT1 expression than those from HS [24] and suggested that the up-regulation of STAT1 expression might result from a host response to HCV infection with IFN-a and/or IFN-c production, because STAT1 itself is one of the IFN-stimulated genes (ISGs) whose expression is up-regulated by IFN-a or IFN-c [27,28], which has been reported to be detected in the sera of patients with CHC [29,30]. The present study has shown that both NK cell subsets from the patients with CHC displayed a higher level of STAT1 expression than those from the HS (Fig.…”