Zania Stamataki, Claire Shannon-Lowe, Jean Shaw, David Mutimer, Alan Rickinson, John Gordon, David H Adams, Peter Balfe and Jane A McKeating. Blood 113:585-93, 2009.
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Hepatitis C is a complex liver infection that some individuals clear spontaneously, yet most people fail to eliminate the virus and become chronically infected (see diagram 1). The reasons for this are not clear. Our work focuses on the humoral and cellular components of immune responses to HCV, with a special interest in B cells (see diagram 2).
We recently demonstrated in collaboration with Chiron (Novartis) that rodents immunised with vaccines prepared from viral envelope glycoproteins could elicit neutralizing responses (Stamataki, 2007).
To further investigate the role of B lymphocytes in infection, we showed that B cells do not become infected with HCV, yet they can internalize the virus, protect it from neutralizing antibodies. B cells can also deliver HCV to hepatocytes in vitro in a highly infectious form.
Our current experiments address the mechanism of HCV interplay with lymphocytes in the context of the liver.
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.
The process of HCV infection.
The role of B cells in HCV infection.
B cells do not support viral replication but protect the virus from enzymatic degradation and antibody neutralization
B cells do support viral trans-infection