Impairment of Gag-Specific CD8+ T-Cell Function in Mucosal and Systemic Compartments of Simian Immunodeficiency Virus mac251- and Simian-Human Immunodeficiency Virus KU2-Infected Macaques

doi:10.1128/JVI.75.23.11483-11495.2001

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Journal of Virology, December 2001, p. 11483-11495, Vol. 75, No. 23
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.23.11483-11495.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Impairment of Gag-Specific CD8⁺ T-Cell Function in Mucosal and Systemic Compartments of Simian Immunodeficiency Virus mac251- and Simian-Human Immunodeficiency Virus KU2-Infected Macaques

Zdenek Hel,¹ Janos Nacsa,¹ Brian Kelsall,² Wen-Po Tsai,¹ Norman Letvin,³ Robyn Washington Parks,¹ Elzbieta Tryniszewska,¹ Louis Picker,⁴ Mark G. Lewis,⁵ Yvette Edghill-Smith,¹ Marcin Moniuszko,¹ Ranajit Pal,⁶ Liljana Stevceva,¹ John D. Altman,⁷ Todd M. Allen,⁸ David Watkins,⁸ José V. Torres,⁹ Jay A. Berzofsky,¹⁰ Igor M. Belyakov,¹⁰ Warren Strober,² and Genoveffa Franchini¹^,^*

Basic Research Laboratory¹ and Metabolism Branch,¹⁰ National Cancer Institute, and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases,² Bethesda, Maryland 20892; Beth Israel Deaconess Medical Center, East Campus, Boston, Massachusetts 02215³; Oregon Health Sciences University, Portland, Oregon 97201⁴; Southern Research Institute, Frederick, Maryland 21701⁵; Advanced Bioscience Laboratories, Inc., Kensington, Maryland 20895⁶; Emory University Vaccine Center at Yerkes, Atlanta, Georgia 30329⁷; Wisconsin Regional Primate Research Center, Madison, Wisconsin 53715⁸; and Department of Medical Microbiology and Immunology, University of California, Davis, School of Medicine, Davis, California 95616⁹

Received 27 November 2000/Accepted 8 August 2001

The identification of several simian immunodeficiency virus mac251 (SIV_mac251) cytotoxic T-lymphocyte epitopes recognizedby CD8⁺ T cells of infected rhesus macaques carrying the Mamu-A*01 moleculeand the use of peptide-major histocompatibility complex tetramericcomplexes enable the study of the frequency, breadth, functionality,and distribution of virus-specific CD8⁺ T cells in the body. To begin to address these issues, we haveperformed a pilot study to measure the virus-specific CD8⁺ and CD4⁺ T-cell response in the blood, lymph nodes, spleen, and gastrointestinallymphoid tissues of eight Mamu-A*01-positive macaques, six ofthose infected with SIV_mac251 and two infected with the pathogenicsimian-human immunodeficiency virus KU2. We focused on the analysisof the response to peptide p11C, C-M (Gag 181), since it was predominantin most tissues of all macaques. Five macaques restricted viralreplication effectively, whereas the remaining three failed tocontrol viremia and experienced a progressive loss of CD4⁺ T cells. The frequency of the Gag 181 (p11C, C $right-arrow$ M) immunodominantresponse varied among different tissues of the same animal andin the same tissues from different animals. We found that thefunctionality of this virus-specific CD8⁺ T-cell population could not be assumed based on the ability tospecifically bind to the Gag 181 tetramer, particularly in themucosal tissues of some of the macaques infected by SIV_mac251that were progressing to disease. Overall, the functionality ofCD8⁺ tetramer-binding T cells in tissues assessed by either measurementof cytolytic activity or the ability of these cells to producegamma interferon or tumor necrosis factor alpha was low and waseven lower in the mucosal tissue than in blood or spleen of someSIV_mac251-infected animals that failed to control viremia. Thedata obtained in this pilot study lead to the hypothesis thatdisease progression may be associated with loss of virus-specificCD8⁺ T-cellfunction.

^* Corresponding author. Mailing address: National Cancer Institute, Basic Research Laboratory, 41/D804, Bethesda, MD 20892.Phone: (301) 496-2386. Fax: (301) 402-0055. E-mail: veffa{at}helix.nih.gov.

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