Abstract
Hepatitis C virus (HCV) infection affects more than 71 million people worldwide. The disease slowly progresses to chronic, long-term liver injury which leads to hepatocellular carcinoma (HCC) in 5 % of infections. The alternative reading frame protein (ARFP/core+1) is encoded by a sequence overlapping the HCV core gene in the +1 reading frame. Its role in hepatitis C pathogenesis and the viral life cycle is unclear, although some observers have related its production to disease progression and the development of HCC. The aim of this study was to determine whether ARFP is immunogenic in patients with chronic HCV genotype 3 infection and to assess whether sero-reactivity is associated with disease progression, particularly to HCC. Immunogenic epitopes within the protein were predicted by a bioinformatics tool, and three −20 aa length-peptides (ARFP-P1, ARFP-P2 and ARFP-P3) were synthesized and used in an avidin-biotin ARFP/core+1 peptide ELISA. Serum samples from 50 patients with chronic HCV genotype 3 infection, 50 genotype-1 patients, 50 HBV patients and 110 healthy controls were tested. Sero-reactivity to the ARFP peptides was also tested and compared in 114 chronic HCV genotype-3 patients subdivided on the basis of disease severity into non-cirrhotic, cirrhotic and HCC groups. Chronic HCV genotype-3 patients showed noticeable rates of reactivity to ARFP and core peptides. Seropositivity rates were 58% for ARFP-P1, 47 % for ARFP-P2, 5.9 % for ARFP-P3 and 100 % for C22 peptides. There was no significant difference between these seroreactivities between HCV genotype-3 patients with HCC, and HCV genotype-3 patients with and without liver cirrhosis. Patients with chronic HCV genotype-3 infection frequently produce antibodies against ARFP/core+1 protein. ARFP peptide reactivity was not associated with disease severity in patients with HCV genotype-3. These results support the conclusion that ARFP/core+1 is produced during HCV infection, but they do not confirm that antibodies to ARFP can indicate HCV disease progression.
Highlights
Hepatitis C virus (HCV) is an enveloped, ssRNA virus, which belongs to the family Flaviviridae, within the genus hepacivirus [1]
HCV-r elated pathogenesis of hepatocellular carcinoma (HCC) is understood to be a long term, multi-step process involving chronic infection, liver fibrosis and cirrhosis followed by malignant transformation [11–14]
Several independent studies showed that chronic HCV patients can elicit specific humoral and cell-mediated immune responses toward alternative reading frame protein (ARFP)/core+1, indirect evidence for its expression during HCV infection [22–28]
Summary
Hepatitis C virus (HCV) is an enveloped, ssRNA virus, which belongs to the family Flaviviridae, within the genus hepacivirus [1]. Chronic HCV infection is a leading cause of hepatocellular carcinoma (HCC), end-stage liver disease and liver-related mortalities [6, 7]. HCV genotype-3, in comparison with other genotypes, is associated with an increased risk of liver steatosis, cirrhosis and HCC [8–10]. HCV-r elated pathogenesis of HCC is understood to be a long term, multi-step process involving chronic infection, liver fibrosis and cirrhosis followed by malignant transformation [11–14]. HCV core protein was mostly implicated in induction of malignant transformation due to its interaction with many intracellular molecules that are involved in oncogenesis [15–19]. Core protein is thought to be involved in the development of liver steatosis as well as insulin resistance [20, 21]. The HCV genome encodes an alternative reading frame protein (ARFP) that overlaps the core gene on the +1 reading frame. Previous studies showed that this sequence may be expressed during the natural course
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