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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 (SIVmac251) cytotoxic T-lymphocyte epitopes recognized by CD8+ T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes 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 have performed a pilot study to measure the virus-specific CD8+ and CD4+ T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIVmac251 and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4+ T cells. The frequency of the Gag 181 (p11C, Cright-arrowM) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8+ T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIVmac251 that were progressing to disease. Overall, the functionality of CD8+ tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIVmac251-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8+ T-cell function.

* 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.

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.


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