title: Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging.
abstract: 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 μM. 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.
authors.affiliation: Department of Medicine, Monash University, Melbourne, Australia.
authors.forename: Edwin
authors.initials: E
authors.lastname: Leeansyah
authors.forename: Paul U
authors.initials: PU
authors.lastname: Cameron
authors.forename: Ajantha
authors.initials: A
authors.lastname: Solomon
authors.forename: Surekha
authors.initials: S
authors.lastname: Tennakoon
authors.forename: Pushparaj
authors.initials: P
authors.lastname: Velayudham
authors.forename: Maelenn
authors.initials: M
authors.lastname: Gouillou
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.forename: Anna
authors.initials: A
authors.lastname: Hearps
authors.forename: Christopher
authors.initials: C
authors.lastname: Fairley
authors.forename: De Villiers
authors.initials: de V
authors.lastname: Smit
authors.forename: Anna B
authors.initials: AB
authors.lastname: Pierce
authors.forename: Jude
authors.initials: J
authors.lastname: Armishaw
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Crowe
authors.forename: David A
authors.initials: DA
authors.lastname: Cooper
authors.forename: Kersten K
authors.initials: KK
authors.lastname: Koelsch
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
authors.forename: John
authors.initials: J
authors.lastname: Chuah
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives*; D000328:Adult; D000375:Aging / Q000187:drug effects*; D019380:Anti-HIV Agents / Q000009:adverse effects*; D023241:Antiretroviral Therapy, Highly Active / Q000009:adverse effects; D016022:Case-Control Studies; D002478:Cells, Cultured; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives; D015224:Dideoxynucleosides / Q000009:adverse effects; D000068679:Emtricitabine; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006678:HIV / Q000472:pathogenicity; D015658:HIV Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000009:adverse effects; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000009:adverse effects*; D016133:Polymerase Chain Reaction; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D012307:Risk Factors; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects / Q000201:enzymology; D059506:Telomere Shortening; D000068698:Tenofovir; D013997:Time Factors; D055815:Young Adult; D015215:Zidovudine / Q000009:adverse effects; D000099227:Abacavir
chemical_list: D000225:Adenine; D019380:Anti-HIV Agents; D003841:Deoxycytidine; D015224:Dideoxynucleosides; D000068679:Emtricitabine; D019259:Lamivudine; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D019098:Telomerase; D000068698:Tenofovir; D015215:Zidovudine; D000099227:Abacavir