Submitted May 29, 2008
Accepted September 16, 2008
Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver derived hepatoma cells
Zania Stamataki, Claire Shannon-Lowe, Jean Shaw, David Mutimer, Alan B. Rickinson, John Gordon, David H. Adams, Peter Balfe, and Jane A McKeating*
Hepatitis C virus Research group, Division of Immunity and Infection, University of Birmingham, Birmingham, West Midlands, United Kingdom
Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, West Midlands, United Kingdom
Liver Laboratories, Division of Immunity and Infection, University of Birmingham, Birmingham, West Midlands, United Kingdom
The Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, West Midlands, United Kingdom
* Corresponding author; email: j.a.mckeating{at}bham.ac.uk.
Hepatitis C virus (HCV) primarily replicates within the liver, leading to hepatitis, fibrosis and hepatocellular carcinoma. Infection is also associated with B cell abnormalities, suggesting an association of the virus with B cells. The infectious JFH-1 strain of HCV can bind primary and immortalised B cells but fails to establish productive infection. However, B cell-associated virus readily infects hepatoma cells showing an enhanced infectivity compared to extracellular virus. B cells express the viral receptors CD81, SR-BI and the C-type lectins DC-SIGN and L-SIGN. Antibodies specific for SR-BI and DC-SIGN/L-SIGN reduced B cell trans-infection, supporting a role for these molecules in B cell association with HCV. Stimulation of B cells with CD40 ligand and IL-4 promoted their ability to trans-infect hepatoma cells. B cell-associated virus is resistant to trypsin proteolysis and HCV specific neutralizing antibodies, consistent with particle internalization. HCV promoted the adhesion of primary B cells to Huh-7 hepatomas, providing a mechanism for B cell retention in the infected liver. In summary, B cells may provide a vehicle for HCV to persist and transmit to the liver.
