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* Department of Pathology and Laboratory Medicine and
Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095;
Geron, Menlo Park, CA 94025; and
Department of Biostatistics, University of California-Los Angeles, School of Public Health, Los Angeles, CA 90095
Telomerase reverse transcribes telomere DNA onto the ends of linear chromosomes and retards cellular aging. In contrast to most normal somatic cells, which show little or no telomerase activity, immune cells up-regulate telomerase in concert with activation. Nevertheless, during aging and chronic HIV-1 infection, there are high proportions of dysfunctional CD8+ CTL with short telomeres, suggesting that telomerase is limiting. The present study shows that exposure of CD8+ T lymphocytes from HIV-infected human donors to a small molecule telomerase activator (TAT2) modestly retards telomere shortening, increases proliferative potential, and, importantly, enhances cytokine/chemokine production and antiviral activity. The enhanced antiviral effects were abrogated in the presence of a potent and specific telomerase inhibitor, suggesting that TAT2 acts primarily through telomerase activation. Our study is the first to use a pharmacological telomerase-based approach to enhance immune function, thus directly addressing the telomere loss immunopathologic facet of chronic viral 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 by the following National Institutes of Health Grants: AG023720 and AI060362 (to R.B.E.), AI52031 (to S.R.F.), AI028697 (University of California-Los Angeles Center for AIDS Research), and by Geron, TA Therapeutics Ltd., and the Frank H. Jernigan Foundation.
2 Current address: 1060 Campus Drive, Stanford, CA 94305.
3 Address correspondence and reprint requests to Dr. Rita B. Effros, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California-Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732. E-mail address: reffros{at}mednet.ucla.edu
4 Abbreviations used in this paper: hTERT, human telomerase catalytic component; TI, telomerase inhibitor; TRAP, telomeric repeat amplification protocol; HBG, human β globin.
5 The online version of this article contains supplemental material.
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