Abstract
We present an analysis of the selective forces acting on two hepatitis C virus genome regions previously postulated to be involved in the viral response to combined antiviral therapy. One includes the three hypervariable regions in the envelope E2 glycoprotein, and the other encompasses the PKR binding domain and the V3 domain in the NS5A region. We used a cohort of 22 non-responder patients to combined therapy (interferon alpha-2a plus ribavirin) for which samples were obtained before initiation of therapy and after 6 or/and 12 months of treatment. A range of 25–100 clones per patient, genome region and time sample were sequenced. These were used to detect general patterns of adaptation, to identify particular adaptation mechanisms and to analyze the patterns of evolutionary change in both genome regions. These analyses failed to detect a common adaptive mechanism for the lack of response to antiviral treatment in these patients. On the contrary, a wide range of situations were observed, from patients showing no positively selected sites to others with many, and with completely different topologies in the reconstructed phylogenetic trees. Altogether, these results suggest that viral strategies to evade selection pressure from the immune system and antiviral therapies do not result from a single mechanism and they are likely based on a range of different alternatives, in which several different changes, or their combination, along the HCV genome confer viruses the ability to overcome strong selective pressures.
Highlights
The hepatitis C virus (HCV) infects approximately 170 million people worldwide and it establishes persistent infection in more than two-thirds of those who contract it [1,2]
Tremendous efforts have been devoted to identify which particular mutations are responsible for HCV resistance to interferon and ribavirin, which has resulted in the identification of several genome regions presumably associated to viral escape but no specific variant(s) have been found to consistently produce this phenotype
Several reports, including our own, have described that the levels of genetic diversity in different HCV genome regions correlate with treatment failure, with higher variability levels before treatment in isolates from non-responders than from responders [35,36,37,38]
Summary
The hepatitis C virus (HCV) infects approximately 170 million people worldwide and it establishes persistent infection in more than two-thirds of those who contract it [1,2]. Hypervariable region 1 (HVR1) consists of a 27 amino acid sequence located at the N-terminus of the protein [10,11] and seems to be involved in target-cell recognition and virus attachment [12]. A fourth highly variable domain (V3), spanning 24 amino acids, is located at the C-terminus of the NS5A protein and appears to be involved in responsiveness to interferon [16,17] Close to this domain there is another important region in the NS5A protein, the protein kinase-R binding domain (PKR-BD), which consists of 66 amino acids and includes a 40 amino acid domain, the putative interferon sensitivity determining region (ISDR). These domains interact with PKR, which is involved in the cellular antiviral response induced by interferon, blocking its antiviral activity [18,19]
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