Influence of specific CD4+ T cells and antibodies on evolution of hypervariable region 1 during acute HCV infection

Background/Aims: Several studies suggest that the evolutionary rate of HVR1 sequence in acute HCV hepatitis derives from the action of a continuous immune-driven positive selection. However, these studies have not been performed examining the relationship between HVR1 evolution and the development of specific immunity to autologous HVR1 sequences. Methods: We performed a longitudinal analysis of HVR1 sequences and specific antibodies and CD4+ T cells in ten HCV acutely infected patients with different clinical outcomes (recovery versus persistence). Results: We showed that although both recovered and chronically evolving individuals developed IFN-γ+ T cells specific for Core and NS sequences, HVR1-specific CD4+ T cells were detected only in patients clearing the virus. On the contrary, all patients displayed anti-HVR1 antibodies that recognized sequences exclusively carried by autologous viruses. Measurements of genetic diversity and the number of non-synonymous per synonymous substitutions within HVR1 sequences before and after antibody appearance showed an increase of these parameters only in concomitance with the appearance of anti-HVR1 antibodies. Conclusions: The evidence that anti-HVR1 antibodies favor HVR1 variant selection suggests that viral complexity in chronically infected patients could represent a virus adaptive strategy to escape the continuous selective process mediated by anti-HVR1 antibodies. © 2007 European Association for the Study of the Liver.