Abstract
Understanding the mechanism of Hepatitis C Virus (HCV) pathogenesis is an important part of HCV research. In this study, the presence of apoptosis in HCV-infected liver and Peripheral Blood Mononuclear Cells (PBMC) from patients positive for anti-HCV antibodies and negative for serum HCV-RNA was investigated. The samples obtained from 21 patients were studied by in situ Hybridization (ISH), Immunofluorescence, TUNEL reaction and caspase 3 activation assays. The findings show that both DNA fragmentation by TUNEL assay and activation of caspase 3 were detected in hepatocytes from patients histologically confirmed as bearing chronic hepatitis or with abnormal ALAT or GGTP as well as in patients with no histological evidences of chronic hepatitis and normalization of transaminases. Apoptotic cells were also detected in PBMC samples by the TUNEL assay. ISH analysis of liver biopsies and PBMC samples showed both positive and negative strands of the HCV genome localized in some cells showing nuclear characteristics of apoptosis such as chromatin margination, condensation and fragmentation. These typical morphological changes of apoptotic cell death were also observed in some hepatocytes showing reaction products suggestive of HCcAg. Data suggest that under certain conditions HCV induces apoptosis in the absence of liver injury. Induction of apoptosis in HCV-infected cells may interfere with viral replication, which may lead to undetectable levels of HCV-RNA in serum.
Highlights
Hepatitis C virus (HCV) is the major cause of nonA, non-B hepatitis that infects 170 million people worldwide[1]
Liver needle biopsy samples were taken at the time of routine diagnostic biopsy from all patients. These 21 patients were selected based upon they showed negative detection of serum HCV-RNA by RT-PCR (Amplicor HCV Amplification Kit 2.0, Roche Diagnostic Systems,Inc) on the same day of the liver biopsy
No sign of apoptosis was detected in hepatocytes from healthy individuals (Fig. 1A)
Summary
Hepatitis C virus (HCV) is the major cause of nonA, non-B hepatitis that infects 170 million people worldwide[1]. Persistent infection occurs in more than 70% of people infected with HCV, 20% of which progress to liver cirrhosis[2]. HCV is an enveloped, positive-strand RNA virus that belongs to the Flaviviridae family. The viral genome (9.6 kb) is translated into a single polyprotein of 3,000 amino acids (aa). The viral products (core, E1, E2, NS2, NS3, NS4A, NS4B, NS5A and NS5B) are processed from this polyprotein by a combination of host and viral proteases. The amino-terminal part is cleaved by host cell proteases and its products, core (HCcAg) and envelope (E1 and E2) proteins, are believed to be the major constituents of HCV virions[3]
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