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* Division of Experimental Medicine and
Department of Medicine, University of California, San Francisco, CA 94110;
Department of Nutritional Sciences, University of California, Berkeley, CA 94720; and
KineMed, Inc., Emeryville, CA 94608
Progressive HIV disease has been associated with loss of memory T cell responses to Ag. To better characterize and quantify long-lived memory T cells in vivo, we have refined an in vivo labeling technique to study the kinetics of phenotypically distinct, low-frequency CD8+ T cell subpopulations in humans. HIV-negative subjects and antiretroviral-untreated HIV-infected subjects in varying stages of HIV disease were studied. After labeling the DNA of dividing cells with deuterated water (2H2O), 2H-label incorporation and die-away kinetics were quantified using a highly sensitive FACS/mass spectrometric method. Two different populations of long-lived memory CD8+ T cells were identified in HIV-negative subjects: CD8+CD45RA–CCR7+CD28+ central memory (TCM) cells expressing IL-7R
and CD8+CD45RA+CCR7–CD28– RA effector memory (TEMRA) cells expressing CD57. In pilot studies in HIV-infected subjects, TCM cells appeared to have a shorter half-life and reduced abundance, particularly in those with high viral loads; TEMRA cells, by contrast, retained a long half-life and accumulated in the face of progressive HIV disease. These data are consistent with the hypothesis that IL-7R+ TCM cells represent true memory CD8+ T cells, the loss of which may be responsible in part for the progressive loss of T cell memory function during progressive HIV infection.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grant RO1 AI43866 (to M.K.H.) and National Institutes of Health Awards U01 AI43641 and R37 AI40312 (to J.M.M.), who is the recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the National Institutes of Health Director’s Pioneer Award Program, part of the National Institutes of Health Roadmap for Medical Research, through Grant DPI OD00329. Funding for the optimization of the low-count techniques was provided by KineMed. The Clinical and Translational Science Institute Clinical Research Center was supported by Grant UL1 RR024131-01 from the National Center for Research Resources, a component of the National Institutes of Health, and National Institutes of Health Roadmap for Medical Research.
2 Current address: Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, U.K.
3 Current address: Department of Medicine, University of Cambridge, Cambridge, U.K.
4 Address correspondence and reprint requests to Dr. Joseph M. McCune, Division of Experimental Medicine, Department of Medicine, University of California, 1001 Potrero Avenue, Building 3, Room 601, San Francisco, CA 94110. E-mail address: mike.mccune{at}ucsf.edu
5 Abbreviations used in this paper: TCM, central memory; TEMRA, RA effector memory; TEM, effector memory; TN, naive; WBC, white blood count differential; GC, gas chromatographic; MS, mass spectrometric; S, sort; NA, not available; FMO, fluorescence minus one; IQR, interquartile range; VL, viral load.
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