3, right). In addition, sequential sequence analyses in two patients with acute-persistent HCV genotype 3a infection showed no evidence of viral escape mutations over a time of one or two years, respectively (data not shown). In line with the results from the cellular assays these data strongly suggest that there is no CD8+ T-cell pressure within the NS5B2841-2849 region in HCV genotype 3a-infected HLA-B27+ patients. Based on our immunological findings, it

is tempting to speculate that in contrast to HCV genotype 1 infection, lack of the immunodominant target of the HLA-B27-restricted CD8+ T-cell responses is associated with loss of the protective effect of HLA-B27 in genotype 3a infection. To address this question, we determined the frequency of HLA-B27 positivity in a large cohort of patients chronically infected RXDX-106 order with either HCV genotype 1 (265 patients) or 3a (98 patients). The frequency of HLA-B27

positivity was significantly higher in patients infected with genotype 3a (12/98 patients, 12.5%) compared with patients infected with genotype 1 (14/265 patients, 5.3%; P = 0.0363) (Fig. 5). selleck inhibitor In this context, it is important to note that the frequency of HLA-B27 positivity in the general German population is ≈8.5% based on the analysis of 11,407 individuals in the German bone marrow registry (compare www.allelefrequencies.net).21 Thus, the protective effect of HLA-B27 in HCV genotype 1

infection is reflected by the low prevalence of HLA-B27 positivity in patients chronically infected with HCV genotype 1. In contrast, HLA-B27 has no protective effect (or may even have a disadvantageous effect) in HCV genotype 3a infection, reflected by the relatively high frequency of HLA-B27 positivity in patients infected with HCV genotype 3a. Importantly, we did not observe a significant difference between the frequencies in genotype 1 or 3a-infected patients for any other HLA-A or HLA-B allele (data not shown). Thus, the different frequency of HLA-B27 in HCV genotype MCE公司 1 versus 3a infection is unique and consistent with the central role of the immunodominant NS5B2841-2849 epitope in mediating the protective effect of HLA-B27 in HCV genotype 1 infection. We have recently linked the protective effect of HLA-B27 in the outcome of HCV infection to an immunodominant HLA-B27-restricted HCV epitope.6 This epitope is located in a highly conserved and functionally constrained region within NS5B, the RNA-dependent RNA polymerase. In our previous study we showed that viral escape from this epitope is limited by viral fitness costs as well as cross-recognition by CD8+ T cells, thus requiring a complex mosaic of two or more mutations for significant viral escape.