期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 209, 期 1, 页码 61-75出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20100388
关键词
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资金
- Howard Hughes Medical Institute
- Deutsche Forschungsgemeinschaft [Schu 2482/1-1, SFB 841 A6]
- Swiss National Science Foundation
- National Institutes of Health [U19-AI066345, U19-AI082630, R01-AI067926-01]
Vigorous proliferative CD4(+) T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4(+) T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4(+) T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4(+) T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4(+) T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4(+) T cells. Instead, broadly directed HCV-specific CD4(+) T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4(+) T cell responses through antiviral therapy.
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