Abstract
Hepatitis C virus (HCV) is a major cause of hepatitis and hepatocellular carcinoma (HCC) world-wide. Most HCV patients have relatively stable disease, but approximately 25% have progressive disease that often terminates in liver failure or HCC. HCV is highly variable genetically, with seven genotypes and multiple subtypes per genotype. This variation affects HCV’s sensitivity to antiviral therapy and has been implicated to contribute to differences in disease. We sequenced the complete viral coding capacity for 107 HCV genotype 1 isolates to determine whether genetic variation between independent HCV isolates is associated with the rate of disease progression or development of HCC. Consensus sequences were determined by sequencing RT-PCR products from serum or plasma. Positions of amino acid conservation, amino acid diversity patterns, selection pressures, and genome-wide patterns of amino acid covariance were assessed in context of the clinical phenotypes. A few positions were found where the amino acid distributions or degree of positive selection differed between in the HCC and cirrhotic sequences. All other assessments of viral genetic variation and HCC failed to yield significant associations. Sequences from patients with slow disease progression were under a greater degree of positive selection than sequences from rapid progressors, but all other analyses comparing HCV from rapid and slow disease progressors were statistically insignificant. The failure to observe distinct sequence differences associated with disease progression or HCC employing methods that previously revealed strong associations with the outcome of interferon α-based therapy implies that variable ability of HCV to modulate interferon responses is not a dominant cause for differential pathology among HCV patients. This lack of significant associations also implies that host and/or environmental factors are the major causes of differential disease presentation in HCV patients.
Highlights
Hepatitis C virus (HCV) is a Hepacivirus that infects hepatocytes and some lymphocytes [1,2]
We previously found that high genetic variation in the consensus sequences of the HCV core, NS3, and NS5A genes was tightly correlated with failure of interferon a plus ribavirin therapy [25,26,27]
Selective pressures associated with hepatocellular carcinoma (HCC) We examined the HCC and cirrhotic control sequences for differences in selective pressure at all 2997 codons using the single likelihood ancestor counting (SLAC) method with the HKY85 substitution mode in order to identify the codons under positive or negative selection [74]. 825 of the 2997 codons were under negative selection and 12 codons were under positive selection in the HCC sequences, while 900 codons were under negative selection and 13 codons under positive selection in the cirrhotic controls (Table 3)
Summary
Hepatitis C virus (HCV) is a Hepacivirus that infects hepatocytes and some lymphocytes [1,2]. It chronically infects about 120–170 million people world-wide, resulting in about 350,000 deaths annually [3,4]. Disease caused by HCV ranges from asymptomatic infection to severe hepatitis, with most people having some degree of ongoing liver damage [1,5]. 25% of chronically infected individuals have progressive disease, where liver pathology proceeds from hepatitis of gradually worsening severity, to hepatic fibrosis, cirrhosis, and often to fatal liver failure or hepatocellular carcinoma (HCC). HCV-induced liver disease is primarily caused by hepatic inflammation and anti-HCV immune responses [6,7,8]. Direct cytopathic effects from viral replication may contribute to disease, but they are believed to be secondary to immune-mediated damage
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