JVI Accepts, published online ahead of print on 30 July 2008

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Radziewicz, H. Articles by Grakoui, A. Search for Related Content PubMed PubMed Citation Articles by Radziewicz, H. Articles by Grakoui, A.

 Previous Article  |  Next Article 

J. Virol. doi:10.1128/JVI.01075-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Impaired HCV specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection

Henry Radziewicz, Chris C. Ibegbu, Huiming Hon, Melissa K. Osborn, Kamil Obideen, Mohammad Wehbi, Gordon J. Freeman, Jeffrey L. Lennox, Kimberly A. Workowski, Holly L. Hanson, and Arash Grakoui^*

Emory Vaccine Center and Department of Microbiology and Immunology, and Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115

^* To whom correspondence should be addressed. Email: arash.grakoui{at}emory.edu.

A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T cell response and viremia persists. The mechanism leading to failure of the HCV specific CD8+ T cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV specific CD8+ T cells during the acute and chronic stages of infection. Although HCV specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV specific CD8+ T cells during the chronic phase, expressed a resting memory phenotype. Apoptosis susceptibility of HCV specific CD8+ T cells was associated with very high programmed death-1 (PD-1) and low CD127 expression, and with significant functional T cell deficits. Further evaluation of the "death phase" of HCV specific CD8+ T cells during acute HCV infection showed that the majority of cells was dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process and despite persistence of virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9 mediated T cell death was also present. This study highlights the importance of cytokine deprivation mediating apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infection.