Category — HIV

Steven Russell Fauce, Beth D. Jamieson , Allison C. Chin, Ronald T. Mitsuyasu , Stan T. Parish, Hwee L. Ng, Christina M. Ramirez Kitchen, Otto O. Yang, Calvin B. Harley , and Rita B. Effros. 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.

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Rita Effros Presentation Summary for SENS (Aubrey de Grey) Conference 6 Sept 2007

R.B. Effros David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer’s disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant “work” required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).

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Rita B. Effros, Experimental Gerontology, Volume 42, Issue 5, 416-420.

Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation.”

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