Inhibition of Telomerase Activity by Human Immunodeficiency Virus (HIV) Nucleos(t)ide Reverse Transcriptase Inhibitors: A Potential Factor Contributing to HIV-Associated Accelerated Aging

被引：106
作者：
Leeansyah, Edwin [1 ,2 ]
Cameron, Paul U. [1 ,2 ,3 ]
Solomon, Ajantha [1 ,2 ]
Tennakoon, Surekha [1 ,2 ]
Velayudham, Pushparaj [1 ,2 ]
Gouillou, Maelenn [4 ]
Spelman, Tim [4 ,5 ]
Hearps, Anna [1 ,2 ]
Fairley, Christopher [6 ]
Smit, De Villiers [7 ]
Pierce, Anna B. [3 ]
Armishaw, Jude [3 ]
Crowe, Suzanne M. [1 ,2 ]
Cooper, David A. [8 ,9 ]
Koelsch, Kersten K. [8 ,9 ]
Liu, Jun-Ping [10 ,11 ]
Chuah, John [12 ,13 ,14 ]
Lewin, Sharon R. [1 ,2 ,3 ]
机构：
[1] Monash Univ, Dept Med, Melbourne, Vic 3004, Australia
[2] Burnet Inst, Ctr Virol, Melbourne, Vic, Australia
[3] The Alfred, Infect Dis Unit, Melbourne, Vic, Australia
[4] Burnet Inst, Ctr Populat Hlth, Melbourne, Vic, Australia
[5] Monash Univ, Sch Publ Hlth & Prevent Med, Melbourne, Vic 3004, Australia
[6] The Alfred, Melbourne Sexual Hlth Ctr, Melbourne, Vic, Australia
[7] The Alfred, Emergency & Trauma Ctr, Melbourne, Vic, Australia
[8] Univ New S Wales, Kirby Inst, Sydney, NSW, Australia
[9] St Vincents Hosp, Sydney, NSW 2010, Australia
[10] Murdoch Childrens Res Inst, Melbourne, Vic, Australia
[11] Univ Melbourne, Dept Genet, Parkville, Vic 3052, Australia
[12] Gold Coast Sexual Hlth Clin, Miami, Australia
[13] Holdsworth House Med Practice, Byron Bay, NSW, Australia
[14] Griffith Univ, Sch Med, Southport, Qld 4215, Australia
来源：
JOURNAL OF INFECTIOUS DISEASES | 2013年 / 207卷 / 07期
基金：
英国医学研究理事会;
关键词：
HIV infection; antiretroviral therapy; telomerase; telomere; aging; CD8(+) T-CELLS; HUMAN HL60 CELLS; ANTIRETROVIRAL NUCLEOSIDE; ALZHEIMERS-DISEASE; UP-REGULATION; IN-VITRO; LENGTH; INFECTION; CANCER; THERAPY;
D O I：
10.1093/infdis/jit006
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
Background. Human immunodeficiency virus (HIV)-infected patients on combination active antiretroviral therapy (cART) are at increased risk of age-related complications. We hypothesized that nucleos(t)ide reverse transcriptase inhibitors (NRTI) may contribute to accelerated aging in HIV-infected individuals on cART via inhibition of telomerase activity. Methods. Telomerase activity and telomere length (TL) were measured by quantitative polymerase chain reaction in vitro in activated peripheral blood mononuclear cells (PBMCs) cultured with NRTI and ex vivo in PBMCs from uninfected patients exposed to NRTI and from HIV-infected patients on NRTI-containing cART. Results. Lamivudine, abacavir, zidovudine, emtricitabine, and tenofovir significantly inhibited telomerase activity in activated PBMCs in vitro. Tenofovir was the most potent inhibitor of telomerase activity and caused greatest shortening of TL in vitro at the therapeutic concentration of 0.3 mu M. PBMCs from HIV-infected patients receiving NRTI-containing cART (n = 39) had significantly lower telomerase activity than HIV-uninfected patients (n = 47; P = .011) and HIV-infected patients receiving non-NRTI-containing cART (n = 11; P < .001). TL was significantly inversely associated with age (P = .009) and the total duration on any NRTI (P = .01). Conclusions. NRTIs and, specifically tenofovir at therapeutic concentrations, inhibit telomerase activity leading to accelerated shortening of TL in activated PBMCs. The relationship between NRTI, reduced telomerase activity, and accelerated aging requires further investigation in HIV-infected individuals on cART.
引用
收藏
页码：1157 / 1165
页数：9
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