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Journal of Virology, March 2009, p. 2728-2742, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02128-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Comparisons of CD8⁺ T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness ^,

Prasanna Jagannathan,¹ Christine M. Osborne,¹ Cassandra Royce,¹ Maura M. Manion,¹ John C. Tilton,¹ Li Li,² Steven Fischer,² Claire W. Hallahan,³ Julia A. Metcalf,¹ Mary McLaughlin,¹ Matthew Pipeling,⁴ John F. McDyer,⁴ Thomas J. Manley,⁵ Jeffery L. Meier,⁶ John D. Altman,⁷ Laura Hertel,⁸ Richard T. Davey Jr.,¹ Mark Connors,^1* and Stephen A. Migueles¹

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,¹ Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland,² Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland,³ Department of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland,⁴ Fred Hutchinson Cancer Research Center, Seattle, Washington,⁵ Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa,⁶ Emory Vaccine Center at Yerkes, Emory University, Atlanta, Georgia,⁷ Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada⁸

Received 8 October 2008/ Accepted 24 December 2008

To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8⁺ T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8⁺ T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8⁺ T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8⁺ T cells were predominantly CD27⁺45RO⁺ for HIV and CD27^–45RA⁺ for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8⁺ T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8⁺ T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8⁺ T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.

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* Corresponding author. Mailing address: LIR, NIAID, NIH, Bldg. 10, Rm. 11B-09, 10 Center Dr. MSC 1876, Bethesda, MD 20892-1876. Phone: (301) 496-8057. Fax: (301) 402-0070. E-mail: mconnors{at}niaid.nih.gov

Published ahead of print on 7 January 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, March 2009, p. 2728-2742, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02128-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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