Findings from Nationwide Children’s are adding to the belief that the Hepatitis C virus, the virus that leads to the contagious liver disease Hepatitis C, is a crafty pathogen. The virus seems to enlist different escape routines in response to different types of immune cells.
Studies of the HCV infection in humans and animal models have documented a critical role of T cell responses in preventing persistent lifelong presence of the virus in the blood. However, in chronic infection, T cell responses fail to destroy the virus. Often, the presence of immune cells known at CD8 T cells pressure the Hepatitis C virus to mutate in order to escape the immune system. The virus also evades CD4+ T helper cells but much less is known about why they fail.
“When comparing resolved and chronic cases of hepatitis C infection, we see that the virus continues to replicate when CD4 T cells fail to help during early stages of infection,” said Chris Walker, PhD, director of the Center for Vaccines and Immunity at The Research Institute and the study’s lead author. “Yet, no comprehensive analysis had yet been performed to explore how common CD4 T cell escape mutations are or to compare their frequency with escape mutations reacting to CD8 T cells.”
To determine if immune escape is a significant factor in driving CD4 T cell failure, researchers in the Center for Vaccines and Immunity analyzed the sequences of viruses from four persistently hepatitis C-infected animals to look for evidence of mutation in regions targeted by CD4 helper versus CD8 killer T cells.
Findings revealed one mutation, a discovery that supports the belief that such CD4-related mutations do occur. However, their continued studies showed that these mutations are much less likely to occur than mutations triggered by CD8 T cells.
“These data are consistent with the hypothesis that hepatitis C-specific CD4 T cells do not exert significant selection pressure to drive amino acid changes in the virus,” said Dr. Walker. “CD8 T cells exert significant selection pressure on hepatitis C virus to drive immune escape, whereas CD4 T cells do not. Our study suggests that other mechanisms drive the early loss of CD4 responses in persistent hepatitis C infection.”
Yet, CD4-related mutations could come back into play as vaccines are developed. “Boosting hepatitis C-specific CD4 T cell responses by vaccination could improve the ability of the host immune response to control infection,” said “However, it might at the same time exert a greater selection pressure on the virus and spawn mutations,” said Dr. Walker.
More research is needed to examine whether escape mutations might play a role in viral persistence when the virus infects a new host.
Fuller MJ, Shoukry NH, Gushima T, Bowen DG, Callendret B, Campbell KJ, Hasselschwert DL, Hughes AL, Walker CM. Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection. Hepatology. 2010 Feb;51(2):378-87.