Abstract
Peginterferon lambda-1a (Lambda), a type III interferon (IFN), acts through a unique receptor complex with limited cellular expression outside the liver which may result in a differentiated tolerability profile compared to peginterferon alfa (alfa). In Phase 2b clinical studies, Lambda administered in combination with ribavirin (RBV) was efficacious in patients with hepatitis C virus (HCV) infection representing genotypes 1 through 4, and was associated with more rapid declines in HCV RNA compared to alfa plus RBV. To gain insights into potential mechanisms for this finding, we investigated the effects of HCV replication on IFN signaling in primary human hepatocytes (PHH) and in induced hepatocyte-like cells (iHLCs). HCV infection resulted in rapid down-regulation of the type I IFN-α receptor subunit 1 (IFNAR1) transcript in hepatocytes while the transcriptional level of the unique IFN-λ receptor subunit IL28RA was transiently increased. In line with this observation, IFN signaling was selectively impaired in infected cells upon stimulation with alfa but not in response to Lambda. Importantly, in contrast to alfa, Lambda was able to induce IFN-stimulated gene (ISG) expression in HCV-infected hepatocytes, reflecting the onset of innate responses. Moreover, global transcriptome analysis in hepatocytes indicated that Lambda stimulation prolonged the expression of various ISGs that are potentially beneficial to antiviral defense mechanisms. Collectively, these observed effects of HCV infection on IFN receptor expression and signaling within infected hepatocytes provide a possible explanation for the more pronounced early virologic responses observed in patients treated with Lambda compared to alfa.
Highlights
For the last decade, the combination of peginterferon alfa and ribavirin (RBV) has been the backbone of therapy for chronic Hepatitis C virus (HCV) infection
Successful treatment, defined as sustained virologic response (SVR) following completion of therapy, is achieved in 40 to 50% of patients infected with hepatitis C virus (HCV) genotype (GT)-1 (-1a and -1b) and 78 to 86% of those infected with HCV GT-2 or -3.[1]. In recent years, highly selective direct acting antivirals (DAAs) targeting the HCV non-structural 3/4A (NS3/4A) protease or the NS5B polymerase have become available marking a new era in the management of chronic HCV infection
Several transcriptional studies conducted on liver biopsy specimens from patients with chronic HCV infection have shown that pre-activated baseline IFN-stimulated gene (ISG) patterns correlate with a poor response to an alfa plus RBV regimen. [13,14,15] There is compelling evidence suggesting that the innate response induced during HCV infection may lead to a refractory state in hepatocytes to further IFN-α stimulation
Summary
The combination of peginterferon alfa (alfa) and ribavirin (RBV) has been the backbone of therapy for chronic Hepatitis C virus (HCV) infection. During HCV infection, IFNs activate the Jak (Janus kinase)-STAT (signal transducer and activator of transcription) pathway to create an antiviral state, both within infected hepatocytes and in neighboring uninfected cells, through the expression and complementary action of numerous IFN-stimulated genes (ISGs).[9, 10] The release of IFNs leads to the recruitment and activation of immune effector cells, through transcription of pro-inflammatory cytokines and chemokines, thereby linking the innate and adaptive arms of immunity crucial to the host ability to control acute HCV infection.[11] Despite the potential effectiveness of these immune defenses, spontaneous clearance of HCV is only observed in 20–30% of infected individuals while the majority of patients progress to chronic infection This disease progression is partially explained by the fact that HCV has evolved various strategies over time to disrupt the host hepatic innate response and evade antiviral defenses.[12] it has been established that the status of the endogenous hepatic IFN system is a strong predictor of responsiveness to alfa. The activation of IFN-α is tightly regulated by several negative feedback loops mediated by cellular factors such as suppressors of cytokine signaling (SOCS) family members and the ubiquitin-specific peptidase 18 (USP18/UBP43).[16,17,18] The significant induction of ISGs and desensitization of hepatocytes to IFN-α may in part explain non-responsiveness to alfa-based treatment in patients
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