Jean-Daniel Abraham

Comparative Vaccine Studies in HLA-A2.1-Transgenic Mice Reveal a Clustered Organization of Epitopes Presented in Hepatitis C Virus Natural Infection

ABSTRACT A polyepitopic CD8+-T-cell response is thought to be critical for control of hepatitis C virus (HCV) infection. Using transgenic mice, we analyzed the immunogenicity and dominance of most known HLA-A2.1 epitopes presented during infection by using vaccines that carry the potential to enter clinical trials: peptides, DNA, and recombinant adenoviruses. The vaccines capacity to induce specific cytotoxic T lymphocytes and interferon gamma-producing cells revealed that immunogenic epitopes are clustered in specific antigens. For two key antigens, flanking regions were shown to greatly enhance the scope of epitope recognition, whereas a DNA-adenovirus prime-boost vaccination strategy augmented epitope immunogenicity, even that of subdominant ones. The present study reveals a clustered organization of HCV immunogenic HLA.A2.1 epitopes and strategies to modulate their dominance.

HCV core, NS3, NS5A and NS5B proteins modulate cell proliferation independently from p53 expression in hepatocarcinoma cell lines

Summary.Several reports have shown that activity and/or expression of p53 can be modulated by Hepatitis C virus (HCV) proteins and may interfere with normal regulation of cell growth. In order to understand the relationship between p53 function and HCV proteins expression, we have investigated potential effects of the core, NS3, NS5A and NS5B proteins on Huh-7 (p53 +/+) and Hep3B (p53 −/−) cell proliferation.The effect of HCV proteins transiently expressed after recombinant-adenoviral infection was analyzed by Western blot, crystal violet and propidium iodide staining.Expression of the core, NS3, NS5A or NS5B proteins inhibited cell proliferation and blocked both cell lines in the G2/M phase of the cell cycle. c-myc and p53 expression were respectively induced and increased in Huh-7 cells only following expression of the Core protein. No expression of p21waf1/cip1 could be detected and expression of cyclin A, cdk2 and p27Kip1 were independent of HCV protein’s expression.Our results show that the effect of core, NS3, NS5A and NS5B on cell proliferation is independent of p53 expression and that only the Core protein, induces the expression of both c-myc and p53.