Functionally Inert HIV-specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

doi:10.1084/jem.192.12.1819

Published online 18 December 2000.

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© The Rockefeller University Press, 0022-1007/2000/12/1819/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 12, December 18, 2000 1819-1832

Original Article

Functionally Inert HIV-specific Cytotoxic T Lymphocytes Do Not Play a Major Role in Chronically Infected Adults and Children

Philip J.R. Goulder^a,b, Yanhua Tang^a, Christian Brander^a, Michael R. Betts^c, Marcus Altfeld^a, Ken Annamalai^d, Alicja Trocha^a, Suqin He^a, Eric S. Rosenberg^a, Graham Ogg^e, Christopher A. O'Callaghan^e, Spyros A. Kalams^a, Ross E. McKinney, Jr.^f, Kenneth Mayer^g, Richard A. Koup^c, Stephen I. Pelton^h, Sandra K. Burchett^b, Kenneth McIntosh^b, and Bruce D. Walker^a
^a Partners AIDS Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
^b Division of Infectious Diseases, The Children's Hospital, Boston, Massachusetts 02115
^c Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, Texas 75390
^d Department of Pediatrics, University of Natal, Durban Congella 4015, South Africa
^e Medical Research Council Human Immunology Unit, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
^f Section of Pediatric Infectious Diseases, Duke University Medical Center, Durham, North Carolina 27710
^g Fenway Community Health Center, Boston, Massachusetts 02115
^h Section of Pediatric Infectious Diseases, Boston Medical Center, Boston, Massachusetts 02118

Correspondence to: Philip J.R. Goulder, Partners AIDS Research Center, Massachusetts General Hospital, 13th St., Bldg. 149, Rm. 5218, Charlestown, MA 02129. Tel:617-726-5787 Fax:617-726-5411 E-mail:goulder{at}helix.mgh.harvard.edu.

The highly sensitive quantitation of virus-specific CD8⁺ T cellsusing major histocompatibility complex–peptide tetramerassays has revealed higher levels of cytotoxic T lymphocytes(CTLs) in acute and chronic virus infections than were recognizedpreviously. However, studies in lymphocytic choriomeningitisvirus infection have shown that tetramer assays may includemeasurement of a substantial number of tetramer-binding cellsthat are functionally inert. Such phenotypically silent CTLs,which lack cytolytic function and do not produce interferon(IFN)- ${gamma}$ , have been hypothesized to explain the persistence ofvirus in the face of a quantitatively large immune response,particularly when CD4 help is impaired. In this study, we examinedthe role of functionally inert CTLs in chronic HIV infection.Subjects studied included children and adults (n = 42) whoseviral loads ranged from <50 to >100,000 RNA copies/ml plasma.Tetramer assays were compared with three functional assays:enzyme-linked immunospot (Elispot), intracellular cytokine staining,and precursor frequency (limiting dilution assay [LDA]) cytotoxicityassays. Strong positive associations were observed between cellnumbers derived by the Elispot and the tetramer assay (r = 0.90).An even stronger association between tetramer-derived numbersand intracellular cytokine staining for IFN- ${gamma}$ was present (r= 0.97). The majority (median 76%) of tetramer-binding cellswere consistently detectable via intracellular IFN- ${gamma}$ cytokinestaining. Furthermore, modifications to the LDA, using a lowinput cell number into each well, enabled LDAs to reach equivalencewith the other methods of CTL enumeration. These data togethershow that functionally inert CTLs do not play a significantrole in chronic pediatric or adult HIV infection.

Key Words: peptide–major histocompatibility complex tetrameric complexes,intracellular cytokine staining, limiting dilution assays, enzyme-linkedimmunospot, CD8⁺ T cells

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