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Journal of Virology, October 2008, p. 9808-9822, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Impaired Hepatitis C Virus (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{triangledown}

Henry Radziewicz,1,2 Chris C. Ibegbu,1 Huiming Hon,2 Melissa K. Osborn,2 Kamil Obideen,2 Mohammad Wehbi,2 Gordon J. Freeman,3 Jeffrey L. Lennox,2 Kimberly A. Workowski,2 Holly L. Hanson,1 and Arash Grakoui1,2*

Emory Vaccine Center and Department of Microbiology and Immunology,1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322,2 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 021153

Received 21 May 2008/ Accepted 22 July 2008

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 levels of 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 were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the 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-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections.

* Corresponding author. Mailing address: Emory University School of Medicine, 954 Gatewood Road, NE, Atlanta, GA 30329. Phone: (404) 727-5850. Fax: (404) 727-7768. E-mail: arash.grakoui{at}emory.edu

{triangledown} Published ahead of print on 30 July 2008.

Journal of Virology, October 2008, p. 9808-9822, Vol. 82, No. 20
0022-538X/08/$08.00+0     doi:10.1128/JVI.01075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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