Telomerase-based pharmacologic enhancement of antiviral function of human CD8+ T lymphocytes.
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.
Fauce
Steven Russell
SR
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Jamieson
Beth D
BD
Chin
Allison C
AC
Mitsuyasu
Ronald T
RT
Parish
Stan T
ST
Ng
Hwee L
HL
Kitchen
Christina M Ramirez
CM
Yang
Otto O
OO
Harley
Calvin B
CB
Effros
Rita B
RB
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015658:HIV Infections / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D009841:Oligonucleotides; D009842:Oligopeptides / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012502:Sapogenins / Q000494:pharmacology*; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism
D004791:Enzyme Inhibitors; C505952:GRN163L peptide; D009841:Oligonucleotides; D009842:Oligopeptides; D012502:Sapogenins; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019098:Telomerase; C061014:cycloastragenol