Sporadic Reappearance of Minute Amounts of HCV RNA after Successful Therapy Stimulates Cellular Immune Responses

Article in Press

Naga Suresh Veerapu, Sukanya Raghuraman, T. Jake Liang, Theo Heller, Barbara Rehermann
Received 26 May 2010; received in revised form 24 September 2010; accepted 22 October 2010. published online 01 November 2010.

Accepted Manuscript

Abstract

Background & Aims
Several studies have reported persistence of hepatitis C virus (HCV) RNA in the circulation after treatment-induced or spontaneous recovery. We investigated whether the HCV RNA represents persistence of HCV infection or re-infection.

Methods
We studied 117 patients that recovered from HCV infection (98 following therapy and 19 spontaneously). A reverse transcriptase (RT)-PCR assay was used to detect the 5’UTR of HCV RNA. T-cell responses were studied by ELISpot analysis of interferon-γ.

Results
Plasma samples from 15% of patients who recovered following treatment and none who recovered spontaneously tested positive for HCV RNA. Lymphocytes from 3 patients that responded to therapy and 1 that recovered spontaneously tested positive. The frequency of HCV RNA detection in plasma correlated inversely with the time after the end of treatment. Post-treatment HCV 5’-UTR sequences matched pre-treatment sequences in 85% of cases. T-cell responses were significantly greater at timepoints with detectable trace amounts of HCV RNA than at timepoints without detectable HCV RNA (P=0.035) and were primarily against nonstructural HCV antigens. The immune hierarchy was preserved over 5 years in patients; post-treatment HCV RNA sequences matched pretreatment sequences, indicating HCV RNA persistence. An altered immune hierarchy with dominant immune responses, shifting from nonstructural to structural antigens, was observed in a single patient. The genotype of the detected post-treatment HCV RNA differed from that of the pretreatment genotype in this patient, indicating re-infection with HCV.

Conclusions
Trace amounts of HCV RNA of pretreatment sequence persisted and re-appeared sporadically in the circulation within 8 years after recovery from hepatitis C but not thereafter, indicating that patients are cured of HCV infection. Reappearance of HCV RNA induced HCV-specific T-cell responses.

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Keywords: IFN, liver disease, virology

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