Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-09, Vol.109 (36), p.14562-14567
• Main Authors: Farci, Patrizia, Wollenberg, Kurt, Diaz, Giacomo, Engle, Ronald E, Lai, Maria Eliana, Klenerman, Paul, Purcell, Robert H, Pybus, Oliver G, Alter, Harvey J
• Format: Article
• Language: English
• Subjects: adaptive immunity; alanine transaminase; Alanine Transaminase - blood; antibodies; Base Sequence; Biological Sciences; chemokine CCL2; chemokine CCL4; Chemokine CCL4 - metabolism; Chemokines; Chemokines - blood; chronic diseases; Chronic hepatitis; chronic hepatitis C; Cloning, Molecular; death; Disease Progression; disease severity; Enzymes; Evolution; Evolution, Molecular; Evolutionary biology; Fibrosis; Hepacivirus; Hepacivirus - genetics; Hepatitis; Hepatitis C; Hepatitis C - complications; Hepatitis C - physiopathology; Hepatitis C virus; Immunoglobulins; Infections; interferon-gamma; Interferon-gamma - blood; Liver; Liver cirrhosis; Liver Cirrhosis - etiology; Liver Cirrhosis - virology; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral - blood; Sequence Analysis, DNA; seroconversion; Statistics, Nonparametric; viremia; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1210592109

Chronic hepatitis C may follow a mild and stable disease course or progress rapidly to cirrhosis and liver-related death. The mechanisms underlying the different rates of disease progression are unknown. Using serial, prospectively collected samples from cases of transfusion-associated hepatitis C, we identified outcome-specific features that predict long-term disease severity. Slowly progressing disease correlated with an early alanine aminotransferase peak and antibody seroconversion, transient control of viremia, and significant induction of IFN-γ and MIP-1β, all indicative of an effective, albeit insufficient, adaptive immune response. By contrast, rapidly progressive disease correlated with persistent and significant elevations of alanine aminotransferase and the profibrogenic chemokine MCP-1 (CCL-2), greater viral diversity and divergence, and a higher rate of synonymous substitution. This study suggests that the long-term course of chronic hepatitis C is determined early in infection and that disease severity is predicted by the evolutionary dynamics of hepatitis C virus and the level of MCP-1, a chemokine that appears critical to the induction of progressive fibrogenesis and, ultimately, the ominous complications of cirrhosis.