Determinants of viral clearance and persistence during acute hepatitis C virus infection

The virological and immunological features of hepatitis C virus (HCV) infec tion were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that p rogressed to chronicity while one subject cleared the virus. In all subject s, viremia was first detectable within 1-2 weeks of inoculation, 1 month or more before the appearance of virus-specific T cells. The subject who clea red the virus experienced a prolonged episode of acute hepatitis that coinc ided with a CD38(+) IFN-gamma (-) CD8(+) T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4(+) T cell response emerge d and the CD8(+) T cells became CD38(-) and started producing IFN-gamma in response to HCV, coinciding with a rapid 100,000-fold decrease in viremia t hat occurred without a corresponding surge of disease activity. Chronic inf ection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4(+) T c ell responses that ultimately waned. In all subjects, viremia was higher at the peak of acute hepatitis than it was when the disease began, and the di sease improved during the viremia. These results provide the first insight into the host-virus relationship in humans during the incubation phase of a cute HCV infection, and they provide the only insight to date into the viro logical and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, th e results suggest that the vigor and quality of the antiviral T cell respon se determines the outcome of acute HCV infection, that the ability of HCV t o outpace the T cell response may contribute to its tendency to persist; th at the onset of hepatitis coincides with the onset of the CD8(+)T cell resp onse, that disease pathogenesis and viral clearance are mediated by differe nt CD8+ T cell populations that control HCV by both cytolytic and noncytoly tic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.