title: Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis.
abstract: 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.
authors: Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. pfarci@niaid.nih.gov
authors: Patrizia
authors: P
authors: Farci
authors: Kurt
authors: K
authors: Wollenberg
authors: Giacomo
authors: G
authors: Diaz
authors: Ronald E
authors: RE
authors: Engle
authors: Maria Eliana
authors: ME
authors: Lai
authors: Paul
authors: P
authors: Klenerman
authors: Robert H
authors: RH
authors: Purcell
authors: Oliver G
authors: OG
authors: Pybus
authors: Harvey J
authors: HJ
authors: Alter
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D001483:Base Sequence; D054407:Chemokine CCL4 / Q000378:metabolism; D018925:Chemokines / Q000097:blood; D003001:Cloning, Molecular; D018450:Disease Progression; D019143:Evolution, Molecular; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000150:complications* / Q000503:physiopathology*; D007371:Interferon-gamma / Q000097:blood; D008103:Liver Cirrhosis / Q000209:etiology* / Q000821:virology; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric
chemical_list: C066507:CCL4 protein, human; D054407:Chemokine CCL4; D018925:Chemokines; D012367:RNA, Viral; D007371:Interferon-gamma; D000410:Alanine Transaminase