HCV genome-wide genetic analyses in context of disease progression and hepatocellular carcinoma

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.

Trial registration: ClinicalTrials.gov NCT00006164.

Figure 1. HCV genome.

The HCV genome contains 5′ and 3′ untranslated regions and a single, long open reading frame that encodes 10 proteins. The mature viral proteins encoded within the open reading frame and their major functions are indicated. Reprinted from under the creative commons license.

Figure 2. Amino acid covariance networks for the HCC and cirrhotic sequences.

Amino acid covariances within alignments of the HCV cirrhotic (left) and HCC (right) sequences were graphed with the covarying positions (nodes) represented as circles and the covariances between the positions (edges) as lines. The size of the nodes is proportional to the number of edges that they contact. Yellow nodes are within structural proteins and green nodes are in non-structural proteins. The amino acid residue position numbered relative to the HCV polyprotein is indicated in the larger nodes.