BACKGROUND: Despite the availability of several direct acting antivirals (DAA) specifically inhibiting different hepatitis C virus (HCV) proteins, treatment of chronic HCV infection is still a challenge also because of the possible selection of resistant viral variants under DAA therapy. Indeed, only the emergence of viruses resistant to the nucleoside inhibitors of the HCV NS5B polymerase (Pol) has not yet been reported, in spite of the fact that in vitro studies have clearly shown that an S282T amino acid change in the Pol protein may confer resistance to these drugs. On the basis of a previous study showing that viral variants resistant to the HCV protease inhibitors are largely present in the liver - but not in the serum - of untreated patients, we investigated the possible natural occurrence of viral populations with the S282T change in the polymerase protein, analyzing viral isolates from liver and serum of HCV genotype 1b naïve patients. METHODS: HCV-1b isolates from liver specimens and serum samples of 10 chronic hepatitis C patients were analyzed by cloning and sequencing. RESULTS: The S282T mutation was not found in any of the viral isolates from either liver or serum samples of all the cases, although a S282G mutation of unknown virological/clinical relevance was detected in 2/19 liver isolates from one patient. CONCLUSIONS: Our study confirms that the natural selection of the S282T mutation is a rare event, thus explaining the lack of emergence and takeover of these variants under drug pressure
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