Why do cytotoxic T lymphocytes fail to eliminate hepatitis C virus? Lessons from studies using major histocompatibility complex class I peptide tetramers

Hepatitis C virus (HCV) infection is a major public health problem, affecti ng an estimated 3% of the world's population, and over 10% in some countrie s. Infection in most cases becomes persistent, and can lead to hepatic infl ammation, fibrosis and liver failure. The T lymphocyte reponse, in particul ar that mediated by cytotoxic T lymphocytes (CTLs), is likely to be involve d in determining the outcome of infection, although its overall role is not clear. The use of major histocompatibility complex (MHC) class I peptide t etrameric complexes (tetramers) to study antiviral CTL responses has revolu tionized our approach tc, the study of human infection. We have used a pane l of MHC class I tetramers to analyse immune responses in HCV-infected indi viduals at various stages of disease. We find that the CTL response against HCV is vigorous in its early phases but dwindles over time both in terms o f lymphocyte number and function. A number of potential explanations for th is 'CTL failure' are discussed.