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

Abstract

The virological and immunological features of hepatitis C virus (HCV) infection were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that progressed to chronicity while one subject cleared the virus. In all subjects, 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 cleared the virus experienced a prolonged episode of acute hepatitis that coincided with a CD38+ IFN-gamma- CD8+ T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4+ T cell response emerged 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 that occurred without a corresponding surge of disease activity. Chronic infection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4+ T cell 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 disease improved during the viremia. These results provide the first insight into the host-virus relationship in humans during the incubation phase of acute HCV infection, and they provide the only insight to date into the virological and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, the results suggest that the vigor and quality of the antiviral T cell response determines the outcome of acute HCV infection, that the ability of HCV to outpace the T cell response may contribute to its tendency to persist; that the onset of hepatitis coincides with the onset of the CD8+ T cell response, that disease pathogenesis and viral clearance are mediated by different CD8+ T cell populations that control HCV by both cytolytic and noncytolytic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.

Figure 1.

Courses of acute HCV infection in five subjects after accidental needlestick exposure to HCV-positive blood. HCV RNA values were expressed as log GEs per milliliter of serum. sALT activity was expressed in U per liter. Total bilirubin levels are expressed as mg/dl and <1.2 mg/dl are identified as negative (−). HCV-specific antibody responses reflect the results of an HCV EIA-2 assay as described in Materials and Methods.

Figure 2.

HCV-specific T cell responses in Subject 1 during asymptomatic, resolving acute HCV infection. (A) Course of infection (see Fig. 1). (B) Percentage of CD8⁺ lymphocytes that were tetramer-positive at each time point. CD8⁺ T cell responses were tested directly ex vivo using HLA-A2 tetramers complexed with five different HLA-A2 restricted epitopes (Table II). CD8⁺ T cell responses against two epitopes (NS3 1073 and NS3 1406 [VA]) were detectable. (C) Percentage of NS3 1406 (VA)-specific CD8⁺ T cells expressing the activation marker CD38. (D) Percentage of CD8⁺ T cells that produce IFN-γ in response to HCV NS3 1406 (VA) (black bars) and NS3 1406 (SG) (white bars). (E) Proliferative CD4⁺ T cell responses against core, NS3, NS4, and NS5 are shown as the sum of all positive stimulation indices (Table III). *Sum of all specific stimulation indices is 56 (see Table III).

Figure 3.

HCV-specific T cell responses during asymptomatic acute HCV infection in Subjects 2 and 3 who progressed to chronicity. (A and D) Courses of infection in Subjects 2 and 3 (see Fig. 1). (B) Percentage of CD8⁺ lymphocytes that were tetramer-positive at each time point. CD8⁺ T cell responses were tested directly ex vivo in Subject 2 using HLA-A2 tetramers complexed with five different HLA-A2–restricted epitopes (Table II). A transient and weak CD8⁺ T cell response was only detectable against a single epitope (NS3 1073). Subject 3 was not studied because she was not HLA-A2 positive. (C and F) Proliferative CD4⁺ T cell responses against core, NS3, NS4, and NS5 are shown as the sum of all positive stimulation indices (Table III). *Sum of all specific stimulation indices is 50.1 (see Table III).

Figure 4.

HCV-specific T cell responses during symptomatic acute HCV infection in Subjects 4 and 5 who progressed to chronicity. (A and B) Courses of infection (see Fig. 1). (B and D) Proliferative CD4⁺ T cell responses were tested against core, NS3, NS4, and NS5 and are shown as the sum of all positive stimulation indices (Table III). *Sum of all specific stimulation indices is 152.2 in Subject 4 and 84.1 in Subject 5 (see Table III).