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Journal of Virology, June 2001, p. 5550-5558, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5550-5558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Sustained Dysfunction of Antiviral CD8+ T Lymphocytes after Infection with Hepatitis C Virus

Norbert H. Gruener,1 Franziska Lechner,2 Maria-Christina Jung,3 Helmut Diepolder,3 Tilman Gerlach,3 Georg Lauer,4 Bruce Walker,4 John Sullivan,5 Rodney Phillips,2 Gerd R. Pape,1,3 and Paul Klenerman2,*

Institute for Immunology, D-80336 Munich,1 and Medical Department II, Klinikum Grosshadern, D-81366 Munich,3 Germany; Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom2; Infectious Diseases Unit and AIDS Research Center, Massachussets General Hospital and Harvard Medical School, Boston, Massachusetts 021294; and Australian Red Cross Blood Service, Sydney 2000, Australia5

Received 23 January 2001/Accepted 12 March 2001

Hepatitis C virus (HCV) sets up persistent infection in the majority of those exposed. It is likely that, as with other persistent viral infections, the efficacy of T-lymphocyte responses influences long-term outcome. However, little is known about the functional capacity of HCV-specific T-lymphocyte responses induced after acute infection. We investigated this by using major histocompatibility complex class I-peptide tetrameric complexes (tetramers), which allow direct detection of specific CD8+ T lymphocytes ex vivo, independently of function. Here we show that, early after infection, virus-specific CD8+ T lymphocytes detected with a panel of four such tetramers are abnormal in terms of their synthesis of antiviral cytokines and lytic activity. Furthermore, this phenotype is commonly maintained long term, since large sustained populations of HCV-specific CD8+ T lymphocytes were identified, which consistently had very poor antiviral cytokine responses as measured in vitro. Overall, HCV-specific CD8+ T lymphocytes show reduced synthesis of tumor necrosis factor alpha (TNF-alpha ) and gamma interferon (IFN-gamma ) after stimulation with either mitogens or peptides, compared to responses to Epstein-Barr virus and/or cytomegalovirus. This behavior of antiviral CD8+ T lymphocytes induced after HCV infection may contribute to viral persistence through failure to effectively suppress viral replication.

* Corresponding author. Mailing address: Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom. Phone: 01865 221335. Fax: 01865 220993. E-mail: klener{at}molbiol.ox.ac.uk.

Journal of Virology, June 2001, p. 5550-5558, Vol. 75, No. 12
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.12.5550-5558.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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