Extended interferon-alpha therapy accelerates telomere length loss in human peripheral blood T lymphocytes
Joel M O'Bryan, James A Potts, Herbert L Bonkovsky, Anuja Mathew, Alan L Rothman, HALT-C Trial Group, Gyongyi Szabo, Barbara F Banner, Maureen Cormier, Donna Giansiracusa, Gloria Borders, Michelle Kelley, Adrian M Di Bisceglie, Bruce Bacon, Brent Neuschwander-Tetri, Elizabeth M Brunt, Debra King, William M Lee, Thomas E Rogers, Peter F Malet, Janel Shelton, Nicole Crowder, Rivka Elbein, Nancy Liston, Karen L Lindsay, Sugantha Govindarajan, Carol B Jones, Susan L Milstein, Anna S Lok, Robert J Fontana, Joel K Greenson, Pamela A Richtmyer, R Tess Bonham, James E Everhart, Leonard B Seeff, Patricia R Robuck, Jay H Hoofnagle, Elizabeth C Wright, Chihiro Morishima, David R Gretch, Minjun Chung Apodaca, Rohit Shankar, Natalia Antonov, Kristin K Snow, Anne M Stoddard, Linda Massey, Teresa M Curto, Margaret C Bell, Deepa Naishadham, Zachary D Goodman, Fanny Monge, Gary L Davis, Guadalupe Garcia-Tsao, Michael Kutner, Stanley M Lemon, Robert P Perrillo, Joel M O'Bryan, James A Potts, Herbert L Bonkovsky, Anuja Mathew, Alan L Rothman, HALT-C Trial Group, Gyongyi Szabo, Barbara F Banner, Maureen Cormier, Donna Giansiracusa, Gloria Borders, Michelle Kelley, Adrian M Di Bisceglie, Bruce Bacon, Brent Neuschwander-Tetri, Elizabeth M Brunt, Debra King, William M Lee, Thomas E Rogers, Peter F Malet, Janel Shelton, Nicole Crowder, Rivka Elbein, Nancy Liston, Karen L Lindsay, Sugantha Govindarajan, Carol B Jones, Susan L Milstein, Anna S Lok, Robert J Fontana, Joel K Greenson, Pamela A Richtmyer, R Tess Bonham, James E Everhart, Leonard B Seeff, Patricia R Robuck, Jay H Hoofnagle, Elizabeth C Wright, Chihiro Morishima, David R Gretch, Minjun Chung Apodaca, Rohit Shankar, Natalia Antonov, Kristin K Snow, Anne M Stoddard, Linda Massey, Teresa M Curto, Margaret C Bell, Deepa Naishadham, Zachary D Goodman, Fanny Monge, Gary L Davis, Guadalupe Garcia-Tsao, Michael Kutner, Stanley M Lemon, Robert P Perrillo
Abstract
Background: 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.
Methods/principal findings: Using 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/significance: Sustained 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.
Trial registration: ClinicalTrials.gov NCT00006164.
Conflict of interest statement
Competing Interests: The authors have read the journal's policy and have the following conflicts. Financial relationships of the authors with Hoffmann-La Roche, Inc., are as follows: H.L. Bonkovsky receives research support. Authors with no financial relationships related to this project are J.M. O'Bryan, J.A. Potts, A. Mathew and A.L. Rothman.
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