Abstract
BackgroundType I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes.Methods/Principal FindingsUsing a flow cytometry-based telomere length assay on peripheral blood mononuclear cell samples from the Hepatitis-C Antiviral Long-term Treatment against Cirrhosis (HALT-C) study, we measured T cell telomere lengths at screening and at months 21 and 45 in 29 Hepatitis-C virus infected subjects. These subjects had failed to achieve a sustained virologic response following 24 weeks of pegylated-interferon-alpha plus ribavirin treatment and were subsequently randomized to either a no additional therapy group or a maintenance dose pegylated-IFNα group for an additional 3.5 years. Significant telomere loss in naïve T cells occurred in the first 21 months in the interferon-alpha group. Telomere losses were similar in both groups during the final two years. Expansion of CD8+CD45RA+CD57+ memory T cells and an inverse correlation of alanine aminotransferase levels with naïve CD8+ T cell telomere loss were observed in the control group but not in the interferon-alpha group. Telomere length at screening inversely correlated with Hepatitis-C viral load and body mass index.Conclusions/SignificanceSustained interferon-alpha treatment increased telomere loss in naïve T cells, and inhibited the accumulation of T cell memory expansions. The durability of this effect and consequences for immune senescence need to be defined.
Highlights
Telomeres are repetitive DNA sequences, consisting of hundreds to thousands of double-stranded repeats, found at both ends of every chromosome [1]
This approach combined with previously described anti-CD45RA and anti-CD57 flowFISH staining allowed for quantitative estimation of average telomere length (TL) and frequency in T cell subpopulations
The delineation of TL changes in T cell CD45RA+/2/CD572 subsets shows that declines in the T cell TL are not shifts in naıve versus memory T cell proportions, but true decreases in TL with the greatest impact on the naıve T cell subsets
Summary
Telomeres are repetitive DNA sequences, consisting of hundreds to thousands of double-stranded repeats, found at both ends of every chromosome [1]. Telomerase assists in TL maintenance and slows telomere erosion during activation-induced proliferation of T lymphocytes [2,3]. Type I interferons (IFN), in addition to anti-viral and anti-proliferative effects, inhibit expression and activity of telomerase [4]. IFN commonly causes lymphopenia [5], which is a stimulus for homeostatic proliferation [6]. Type I interferons have pleiotropic effects on host cells, including inhibiting telomerase in lymphocytes and antiviral activity. We tested the hypothesis that long-term interferon treatment would result in significant reduction in average telomere length in peripheral blood T lymphocytes
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