Clearance of low levels of HCV viremia in the absence of a strong adaptive immune response

Abstract

Spontaneous clearance of hepatitis C virus (HCV) has frequently been associated with the presence of HCV-specific cellular immunity. However, there had been also reports in chimpanzees demonstrating clearance of HCV-viremia in the absence of significant levels of detectable HCV-specific cellular immune responses. We here report seven asymptomatic acute hepatitis C cases with peak HCV-RNA levels between 300 and 100,000 copies/ml who all cleared HCV-RNA spontaneously. Patients were identified by a systematic screening of 1176 consecutive new incoming offenders in a German young offender institution. Four of the seven patients never developed anti-HCV antibodies and had normal ALT levels throughout follow-up. Transient weak HCV-specific CD4+ T cell responses were detectable in five individuals which did not differ in strength and breadth from age- and sex-matched patients with chronic hepatitis C and long-term recovered patients. In contrast, HCV-specific MHC-class-I-tetramer-positive cells were found in 3 of 4 HLA-A2-positive patients. Thus, these cases highlight that clearance of low levels of HCV viremia is possible in the absence of a strong adaptive immune response which might explain the low seroconversion rate after occupational exposure to HCV.

Figure 1

Biochemical, virological and immunological course of acute hepatitis C in asymptomatic patients with spontaneous clearance: patients with spontaneous clearance in the absence of anti-HCV. HCV-RNA levels, ALT levels and T cell responses are shown. Coloured bars show the sum of SI values of the proliferation assay and the sum of specific interferon-gamma spots (spots in the presence of antigen – spots in the medium control) against 5 individual HCV proteins (HCV-core, HCV-NS3, HCV-helicase, HCV-NS4, HCV-NS5a). In addition, the number of individual proteins tested positive at the respective time point is shown for each assay. Interferon gamma ELISPOT responses were also tested against a panel of synthetic peptides representing class I and class II T cell epitopes derived from conserved regions of HCV with a cumulative HLA coverage > 85%. These assays were performed in an independent second laboratory ("Pep-Screen ELISPOT"; Vienna lab). The number of peptides tested positive in this assay is also given.

Figure 2

Biochemical, virological and immunological course of acute hepatitis C in asymptomatic patients with spontaneous clearance: patients who developed anti-HCV antibodies.

Figure 3

Peptide screen in patient 36. Only subject #36 mounted a robust multispecific response against at least 5 peptides after clearance of HCV at two independent time points (figure 2). Patient #1 tested positive for one HCV-class II peptide at the first time-point investigated and was negative for all peptides on subsequent time points. Patients #5, #10, #13, #27, and #80 tested negative for all peptides at all time-points investigated. All other patients tested negative in this assay.