Our results help to resolve apparent contradictions in the literature concerning the immunosuppressive effects of HCV core protein. We found that HCV core protein expressed in hepatocytes does not affect T cell activation, which agrees with a separate study using an adenovirus vector.13
Different conclusions were drawn, however, from experiments in which expression of HCV core protein, as mediated by vaccinia virus, suppressed a CTL immune response in mice.7
These contradictory findings may be due to differences between the adenoviral and vaccinia viral vectors in terms of hepatocyte tropism and infection of immune cells.
We propose that HCV core protein does not alter T cell function when expressed in hepatocytes, but rather, does so when expressed in leukocytes, including T cells. This position is supported by the observation that T cells expressing HCV core protein produced low amounts of cytokines, including IL-2, and showed increased sensitivity to Fas-mediated apoptosis.12,25,26
The role of HCV core protein in myeloid lineage cells is supported by the finding that human dendritic cells transduced with an adenovirus coding for HCV core and E1 proteins were poor stimulators for proliferation of allogeneic and autologous T cells.27
In addition, the proliferation of T cells and IFN-γ production in mixed lymphocyte reactions with HCV core-expressing macrophages were inhibited.28
Rigorous analysis of T cell biology during HCV infection in vivo
is difficult because chimpanzee is the only animal model of HCV infection. In liver and blood samples derived from chronic hepatitis C patients, apoptosis of T cells has been reported to be increased in comparison with normal samples.21,22
Also, mitogen-activated monocytes from chronic hepatitis C patients induced CD4+
T cell apoptosis in a co-culture system.29
These studies appear to support the animal and in vitro
experiments suggesting that HCV is immunosuppressive through induction of T cell apoptosis.
T cell apoptosis has been proposed to occur preferentially in the liver,30
and, although bone marrow-derived cells seem to be the main players in intrahepatic CD8+
T cell apoptosis, Ag expression in liver parenchymal cells is important for promoting the intrahepatic trapping of CD8+
In culture, hepatocytes promoted activation-induced cell death of T cells in an intercellular adhesion molecule-1 (ICAM-1)-dependent manner.32
ICAM-1 is constitutively expressed in hepatic sinusoids and was over-expressed in hepatitis C-infected liver.33,34
This suggests an alternative model in which antigen presentation in hepatocytes promotes T cell apoptosis and HCV infection of the liver causes increased ICAM-1 expression, thereby promoting T cell apoptosis.
Our data are inconsistent with this latter model. While abundant evidence links HCV core expression to T cell apoptosis, in our experimental system in which HCV core expression was strictly limited to hepatocytes, no effect of HCV core protein on either apoptosis or activation of CD8+ T cells was observed. We conclude that, while HCV core protein might manipulate the T cell response by acting in immune cells, it does not do so in hepatocytes.