Evidence for sequence selection within the non-structural 5A gene of hepatitis C virus type 1b during unsuccessful treatment with interferon-alpha

Resistance of the hepatitis C virus (HCV) to interferon-alpha (IFN-alpha) t herapy in patients with hepatitis C maybe genetically controlled by an IFN sensitivity-determining region (ISDR) within the non-structural 5A (NS5A) g ene. To assess whether HCV 1b strains carrying a 'resistant' type of ISDR a re selected during unsuccessful IFN therapy, we analysed the evolution of t he NS5A quasispecies, as detected by the clonal frequency analysis techniqu e, and of the ISDR sequence by nucleotide sequence determination, in 11 pat ients showing no virological response during two consecutive cycles of IFN- alpha therapy, IFN-resistant patients had a homogeneous ISDR quasispecies w ith sequences identical to those described as resistant-' or 'intermediate- ' type ISDR, After retreatment with IFN, further selection towards a homoge neous viral population was observed and 10 out of 11 patients had only one variant of HCV with no or just one single amino acid mutation within the IS DR sequence, Treatment and retreatment with IFN was associated in our nonre sponder patients with evolution of the ISDR quasispecies towards a rather h omogeneous viral population carrying a conserved or minimally mutated ISDR motif, supporting the idea that this motif may be relevant for IFN resistan ce in HCV 1b-infected individuals.