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.

Original publication




Journal article


Proc Natl Acad Sci U S A

Publication Date





14562 - 14567


Alanine Transaminase, Base Sequence, Chemokine CCL4, Chemokines, Cloning, Molecular, Disease Progression, Evolution, Molecular, Hepacivirus, Hepatitis C, Interferon-gamma, Liver Cirrhosis, Molecular Sequence Data, RNA, Viral, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, DNA, Statistics, Nonparametric