Telomerase activity of HIV-1-specific CD8+ T cells: constitutive up-regulation in controllers and selective increase by blockade of PD ligand 1 in progressors

被引:58
作者
Lichterfeld, Mathias [1 ,2 ,3 ]
Mou, Danlei [1 ,2 ]
Cung, Thai Duong Hong [1 ,2 ]
Williams, Katie L. [1 ,2 ]
Waring, Michael T. [1 ,2 ,4 ]
Huang, Jinghe [1 ,2 ]
Pereyra, Florencia [1 ,2 ]
Trocha, Alicja [1 ,2 ]
Freeman, Gordon J. [5 ]
Rosenberg, Eric S. [1 ,2 ,3 ]
Walker, Bruce D. [1 ,2 ,4 ]
Yu, Xu G. [1 ,2 ]
机构
[1] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02129 USA
[2] Harvard Univ, Massachusetts Gen Hosp, Ctr AIDS Res, Boston, MA 02115 USA
[3] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02129 USA
[4] Howard Hughes Med Inst, Chevy Chase, MD USA
[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1182/blood-2008-01-135442
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Exhaustion of virus-specific T cells may play an important role in the pathophysiology of chronic viral infections. Here, we analyzed telomere length and telomerase activity in HIV-1-specific CD8(+) T cells from progressors or controllers to determine underlying molecular pathways of T-cell exhaustion and senescence. Telomere lengths of HIV-1-specific CD8(+) T cells from progressors were significantly shorter compared with autologous cytomegalovirus (CMV)/Epstein-Barr virus (EBV)-specific CD8(+) T cells or bulk CD8(+) T cells, while telomere lengths from controllers significantly exceeded those of autologous bulk CD8(+) T cells and reached a similar level as HIV-1-specific CD8(+) T cells collected during primary HIV-1 infection. Telomere length stabilization in controllers corresponded to high levels of constitutive telomerase activity, which was associated with preservation of cytotoxic and proliferative properties. Conversely, limited constitutive telomerase activity was observed in HIV-1 specific CD8(+) T cells from progressors, although an increase in both telomere length and telomerase activity was achieved in antigenic-peptide-stimulated cells from progressors after blocking the PD-1/PD ligand 1 (PD-L1) pathway. Collectively, these data suggest a causal role of telomere shortening for the functional deficiencies of HIV-1-specific CD8(+) T cells in chronic progressive infection, while high constitutive telomerase activities appears to contribute to maintenance of polyfunctional HIV-1-specific CD8(+) T cells from HIV-1 controllers. (Blood. 2008; 112: 3679-3687)
引用
收藏
页码:3679 / 3687
页数:9
相关论文
共 45 条
[1]   Fully Differentiated HIV-1 Specific CD8+T Effector Cells Are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection [J].
Addo, Marylyn M. ;
Draenert, Rika ;
Rathod, Almas ;
Verrill, Cori L. ;
Davis, Benjamin T. ;
Gandhi, Rajesh T. ;
Robbins, Gregory K. ;
Basgoz, Nesli O. ;
Stone, David R. ;
Cohen, Daniel E. ;
Johnston, Mary N. ;
Flynn, Theresa ;
Wurcel, Alysse G. ;
Rosenberg, Eric S. ;
Altfeld, Marcus ;
Walker, Bruce D. .
PLOS ONE, 2007, 2 (03)
[2]   Opinion - Will telomere erosion lead to a loss of T-cell memory? [J].
Akbar, AN ;
Beverley, PCL ;
Salmon, M .
NATURE REVIEWS IMMUNOLOGY, 2004, 4 (09) :737-743
[3]   Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover [J].
Almeida, Jorge R. ;
Price, David A. ;
Papagno, Laura ;
Arkoub, Zaina Ait ;
Sauce, Delphine ;
Bornstein, Ethan ;
Asher, Tedi E. ;
Samri, Assia ;
Schnuriger, Aurelie ;
Theodorou, Ioannis ;
Costagliola, Dominique ;
Rouzioux, Christine ;
Agut, Henri ;
Marcelin, Anne-Genevieve ;
Douek, Daniel ;
Autran, Brigitte ;
Appay, Victor .
JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (10) :2473-2485
[4]   Immune activation and inflammation in HIV-I infection: causes and consequences [J].
Appay, V. ;
Sauce, D. .
JOURNAL OF PATHOLOGY, 2008, 214 (02) :231-241
[5]   HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells [J].
Betts, Michael R. ;
Nason, Martha C. ;
West, Sadie M. ;
De Rosa, Stephen C. ;
Migueles, Stephen A. ;
Abraham, Jonathan ;
Lederman, Michael M. ;
Benito, Jose M. ;
Goepfert, Paul A. ;
Connors, Mark ;
Roederer, Mario ;
Koup, Richard A. .
BLOOD, 2006, 107 (12) :4781-4789
[6]   Telomeres and telomerase: their mechanisms of action and the effects of altering their functions [J].
Blackburn, EH .
FEBS LETTERS, 2005, 579 (04) :859-862
[7]   Mechanism of telomerase induction during T cell activation [J].
Bodnar, AG ;
Kim, NW ;
Effros, RB ;
Chiu, CP .
EXPERIMENTAL CELL RESEARCH, 1996, 228 (01) :58-64
[8]   Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy [J].
Casazza, JP ;
Betts, MR ;
Picker, LJ ;
Koup, RA .
JOURNAL OF VIROLOGY, 2001, 75 (14) :6508-6516
[9]   Telomere measurement by quantitative PCR [J].
Cawthon, RM .
NUCLEIC ACIDS RESEARCH, 2002, 30 (10) :e47
[10]   Genetic manipulation of telomerase in HIV-specific CD8+ T cells:: Enhanced antiviral functions accompany the increased proliferative potential and telomere length stabilization [J].
Dagarag, M ;
Evazyan, T ;
Rao, N ;
Effros, RB .
JOURNAL OF IMMUNOLOGY, 2004, 173 (10) :6303-6311