Hepatitis C virus load and expression of a unique subset of cellular genes in circulating lymphoid cells differentiate non‐responders from responders to pegylated interferon alpha–ribavirin treatment

Pham, Tram N. Q.; Lin, D.M.; Mulrooney‐Cousins, Patricia M.; Churchill, Norma D.; Kowala‐Piaskowska, Arleta; Mozer‐Lisewska, Iwona; Machaj, A; Pazgan−Simon, Monika; Zalewska, Małgorzata; Simon, Krzysztof; King, Dawn; Reddy, S. Bharati; Michalak, Tomasz I.

doi:10.1002/jmv.23481

Cited by 15 publications

(12 citation statements)

References 31 publications

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“…Our results agree with those of Pham et al [46], who analyzed peripheral blood mononuclear cells (PBMC) before peg-IFN-a2b-ribavirin combination therapy found significantly lower TLR4, 5, and 7 levels in responder patients, suggesting potentially inverse effects of these genes on anti-HCV immunity.…”

Section: Discussionsupporting

confidence: 95%

Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients

et al. 2015

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Egypt has the highest prevalence of hepatitis C virus (HCV) in the world. It has been suggested that not only the virus but also the interaction between the virus and the host immune system is important in determining the course of the infection and the response to interferon (IFN)-based therapy. While the adaptive immune system plays a critical role in HCV infection, the innate immune system has only been recognized recently. Toll-like receptors (TLRs) form the cornerstone of the innate immune response. Interleukin-10 (IL-10) is one of the upstream regulators of TLR4. A possible interplay between TLR4 and IL-10 has been suggested. The present study aimed to investigate the role of single-nucleotide polymorphisms (SNPs) in TLR4 and IL-10-1082 and the expression levels of these proteins in predicting the response to treatment in chronic HCV patients. A total of 83 chronic HCV-infected Egyptian patients treated with peg-IFN-a2b-ribavirin combination therapy and 40 healthy subjects were included in this study. SNPs in the TLR4 rs2149356 and IL-10-1082 genes and their serum levels were assessed. Within the responders group, T/T and A/A genotypes were the significantly most frequent genotypes of TLR4 and IL-10-1082, respectively. Moreover, a higher frequency of T/T and A/A was found to be associated with lower serum TLR4 and IL-10 levels in our responder patients. In addition, subjects with the T/T genotype in the healthy control group had a lower serum TLR4 level than those with other genotypes. We conclude that the SNPs

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Section: Discussionsupporting

confidence: 95%

Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients

et al. 2015

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“…Previously, it was shown that the expression levels of ISG mRNA in hepatocytes or in peripheral blood are associated with the outcome of IFN-based therapy for chronic HCV infection (11,22,23). However, the predictive signature (21-probe set) did not include any ISG, indicating that baseline expression of ISG cannot predict viral relapse after successful IFN-based therapy.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling To Predict and Assess the Consequences of Therapy-Induced Virus Eradication in Chronic Hepatitis C Virus Infection

Hou

Oord

Groothuismink

et al. 2014

J Virol

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Systems biology has proven to be a powerful tool to identify reliable predictors of treatment response in chronic hepatitis C virus (HCV) infection. In the present study, we studied patients with chronic HCV infection who responded to interferon (IFN)-based therapy, as evidenced by an absence of HCV RNA at the end of treatment, and focused on two issues that have not received much attention. First, we evaluated whether specific genes or gene expression patterns in blood were able to distinguish responder patients with a viral relapse from responder patients who remained virus negative after cessation of treatment. We found that patients with chronic HCV infection who were sustained responders and relapsers after IFN-based therapy showed comparable baseline clinical parameters and immune compositions in blood. However, at baseline, the gene expression profiles of a set of 18 genes predicted treatment outcome with an accuracy of 94%. Second, we examined whether patients with successful therapyinduced clearance of HCV still exhibited gene expression patterns characteristic of HCV or whether normalization of their transcriptome was observed. We observed that the relatively high expression levels of IFN-stimulated genes (ISGs) in patients with chronic HCV infection prior to therapy were reduced after successful IFN-based antiviral therapy (at 24 weeks of follow-up). These ISGs included the CXCL10, OAS1, IFI6, DDX60, TRIM5, and STAT1 genes. In addition, 1,428 differentially expressed non-ISGs were identified in paired pre-and posttreatment samples from sustained responders, which included genes involved in transforming growth factor beta (TGF-␤) signaling, apoptosis, autophagy, and nucleic acid and protein metabolism. Interestingly, 1,424 genes with altered expression levels in responder patients after viral eradication were identified, in comparison to normal expression levels in healthy individuals. Additionally, aberrant expression levels of a subset of these genes, including the interleukin-32 (IL-32), IL-16, CCND3, and RASSF1 genes, were also observed at baseline. Our findings indicate that successful antiviral therapy for patients with chronic HCV infection does not lead to normalization of their blood transcriptional signature. The altered transcriptional activity may reflect HCV-induced liver damage in previously infected individuals. IMPORTANCETools to predict the efficacy of antiviral therapy for patients with HCV infection are important to select the optimal therapeutic strategy. Using a systems biology approach, we identify a set of 18 genes expressed in blood that predicts the recurrence of HCV RNA after cessation of therapy consisting of peginterferon and ribavirin. This set of genes may be applicable as a useful biomarker in clinical decision-making, since the number of genes included in the predictor is small and the correct prediction rate is high (94%). In addition, we observed that the blood transcriptional profile in patients with chronic HCV infection who were successfully treated is not n...

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“…These cytokines have also been reported to be regulated by activin-A [36]. Moreover, activin-A has been reported to modulate the release of INF- γ [44], which plays an important role in controlling CHC following PEG-INF- α based therapy [45]. Consequently, the observed significant alteration in activin-A and follistatin after 4, 12, and 24 weeks of treatment could be mediated by the therapy used.…”

Section: Discussionmentioning

confidence: 99%

Serum Activins and Follistatin during the Treatment of Chronic Hepatitis C Genotypes 1 and 4 and Their Correlations with Viral Load and Liver Enzymes: A Preliminary Report

Refaat

El-Shemi

Ashshi

et al. 2014

Gastroenterology Research and Practice

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Aims. To measure the effect of pegylated interferon-α therapy on serum activin-A, activin-B, and follistatin and their correlation with viral load and liver fibrosis in chronic hepatitis C (CHC). Methods. This study was cross-sectional and sera were collected from 165 participants classified into 7 groups: 40 healthy negative control, 33 treatment naïve patients as positive control, 19 patients at week 4, 22 at week 12, and 19 at week 24 of treatment initiation and 21 responders and 11 nonresponders at the end of 48-week treatment protocol. Serum candidate proteins were measured using ELISA and liver fibrosis was assessed by AST platelet ratio index (APRI). Results. CHC significantly increased activins and decreased follistatin compared to negative control (P < 0.05). Activin-A and follistatin levels returned to the levels of negative control group at weeks 4, 12, and 24 following treatment initiation and were significantly different from positive control (P < 0.05). Both proteins were significantly different between responders and nonresponders. Activin-A correlated positively and significantly with the viral load and APRI. Conclusion. CHC modulates serum activin-A and follistatin and they appear to be influenced by pegylated interferon-α therapy. Further studies are needed to explore the role of activins in CHC.

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Hepatitis C virus load and expression of a unique subset of cellular genes in circulating lymphoid cells differentiate non‐responders from responders to pegylated interferon alpha–ribavirin treatment

Cited by 15 publications

References 31 publications

Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients

Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients

Gene Expression Profiling To Predict and Assess the Consequences of Therapy-Induced Virus Eradication in Chronic Hepatitis C Virus Infection

Serum Activins and Follistatin during the Treatment of Chronic Hepatitis C Genotypes 1 and 4 and Their Correlations with Viral Load and Liver Enzymes: A Preliminary Report

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