312 ROLE OF INTRAHEPATIC INNATE IMMUNE ACTIVATION IN CHRONIC HEPATITIS C: THE ROLE OF NK, NKT AND DENDRITIC CELLS AND THE IMPACT OF IMMUNE SUPPRESSION

Abstract

to study the impact of sequence differences in the infection source on susceptibility to chronic HCV infection. The study was possible because three distinct viral variants were present in the infection source. Methods: The genomic region covering the nonstructural protein NS3 was sequenced from the infection source as well as from 115 HLA-typed patients 30 years after the initial infection. Results: Phylogenetic analysis of sequences revealed existence of three distinct variants (termed I, II and III) in the common source outbreak that were already present in the infection source. By analysis of HLA-class I-associated mutations a novel HLA-B*07restricted CD8 epitope (WPAPSGARSL1111–1120) was identified in NS3. Mutations were selected in position 2 and 5 of the epitope in the presence of HLA-B*07 (p < 0.001 and p=0.009). Interestingly, variant III from the infection source already harbored the S5P substitution. Importantly, although the frequency of HLA-B*07 was similar in patients infected with variant I or II (20% and 22%) there was a higher frequency of HLA-B*07 in the group of patients infected with variant III (36%). Conclusion: Presence of the putative S5P escape mutation in the HLA-B7-restricted CD8 epitope may have increased the suseptibility to variant III in HLA-B*07-positive individuals from this common source outbreak. This study highlights that subtle differences in the infection source may have profound effects on the ability to clear HCV infection in the presence of particular HLA-class I-alleles.