Hepatitis C pathogenesis: mechanisms of viral clearance and liver injury

1. The development of hepatitis C virus (HCV) quasispecies has a number of biological consequences, including the development of escape mutants to humoral or cellular immunity, the generation of "defective" viral particles, variable cell tropism, and the development of drug resistance. 2. Accumulating evidence shows that HCV affects the early innate immune response mediated by natural killer and dendritic cells. 3. Recent data suggest that clearance of HCV bestows antibody to HCV immunity that affords partial protection against persistent infection. However, after spontaneous recovery from HCV infection, titers of HCV-specific antibodies decline and disappear in a subset of patients, whereas viral-specific CD4(+) and CD8(+) T-cell responses persist for decades. 4. HCV-specific CD8(+) T-cell responses are phenotypically and functionally diverse and may be associated with either viral eradication or chronic hepatic immunopathologic states. 5. Novel HCV genome-wide screening approaches have shown that the breadth of the immune response is considerably greater than was initially appreciated using more conventional assays, but why the majority of patients remain chronically infected despite the presence of viral-specific immune responses remains undefined.