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.

Fueling fibrosis in chronic hepatitis C

“…How do the findings reported by Farci et al (5) relate to the general HCVinfected population? The patients with rapidly progressing disease they studied received multiple transfusions, and were likely infected with an exceptionally hightiter virus inoculum.…”

“…The three patients with rapidly progressing disease studied by Farci et al (5) are unusual in that in each died of endstage liver disease within 7 y of infection.…”

“…This could initiate a feed-forward autocrine loop, as activated HSCs have receptors for MCP-1 that exert mitogenic and fibrogenic influences on these cells (14). An important role for MCP-1, strongly implicated by Farci et al (5), is supported by a previous study showing that a SNP in the MCP-1 promoter predisposes HCV-infected patients to more severe hepatic inflammation and fibrosis (15). We have shown that the intrahepatic expression of MCP-1 is sixfold higher in chronic hepatitis C than in normal liver (16), and serum levels of MCP-1 are also increased in liver transplant recipients with particularly severe recurrent HCV infection (17).…”

“…Against this sobering backdrop, the two most pressing questions today are why the immune systems of most persons fail to clear the virus when they are first infected, resulting in lifelong virus persistence in as many as 70%, and why some chronically infected persons develop progressive, lifethreatening liver disease whereas others do not. In PNAS, Farci et al, leaders in the field since the early days of non-A, non-B hepatitis, provide insight into this important second question (5).…”

Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue

“…HCV circulates in vivo as a dynamic distribution of closely related viral variants that are commonly referred to as "quasispecies" (2). Such diversity confers a remarkable advantage to the virus under host selective constraints (3)(4)(5). One of the most important features of HCV is its extraordinary ability to persist in up to 80% of infected individuals (6).…”