Is hepatitis C virus NS3 protease quasispecies heterogeneity predictive of progression from cirrhosis to hepatocellular carcinoma?

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We investigated whether an HCV NS3 protease quasispecies heterogeneity was associated with progression from viral cirrhosis to hepatocellular carcinoma (HCC). The NS3 protease quasispecies structure of 10 HCV-1b cirrhotic patients (controls) was compared with that of 10 paired HCV-1b cirrhotic patients who displayed progression to HCC (cases). NS3 protease genetic complexity and diversity did not differ significantly between cases and controls. Amino acid substitutions were detected at 20 (11%) and 25 (14%) sites in at least two variants of the NS3 protease in cases and controls, respectively. Significant differences in the percentage of substituted clones were observed for 10 NS3 sites. Mutations Y56F, I71V, T72I, Q86P, P89S, S101G/D, R117H, S122G/T/N, V132I and V170I were more frequently observed in the NS3 protease sequences of controls than in those of cases. Residue V107 was substituted in NS3 cases but not in controls. However, these differences did not allow the definition of a specific NS3 profile related to HCC occurrence. The NS3 secondary structure B1-1 previously identified as potentially predictive of HCC was identified with a higher frequency in cases quasispecies (84.2%) than in controls (55.9%; P < 0.05). Our results suggest that there may be a relationship to fibrosis progression when diversity parameters are considered together with secondary structure profiles. Further investigations are required to determine the cellular interactions of HCV NS3 protease in the context of carcinogenesis.

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