|
7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV13–16 November 2005, Dublin, Ireland |
Antiretrovirals used to treat HIV infection induce premature senescence in human fibroblasts
M Caron1, M Auclair1, C Vigouroux1,2 and J Capeau1,2
1INSERM U680 UPMC, Paris, France; 2Tenon Hospital, Paris, France
Antiviral Therapy 2005; Supplement 3:L13 (abstract no.18)
OBJECTIVES: The aim of our work was to check whether a series of protease inhibitors [PIs: indinavir (IDV) and nelfinavir (NFV)] and nucleoside reverse transcriptase inhibitors [NRTIs: stavudine (d4T), zidovudine (ZDV) and lamivudine (3TC)] could induce premature senescence in cultured human cells.
METHODS: The cellular ageing process was studied in cultured skin fibroblasts from healthy subjects by testing cellular proliferation (population doubling level (PDL) and BrdU staining), senescence (β-galactosidase activity at pH 6, protein expression of the cell cycle checkpoint inhibitors p16INK4 and p21 and cell morphology), mitochondrial mass and function (Mitotracker labelling, JC1 aggregation) and production of reactive oxygen species (ROS).
RESULTS: A chronic treatment (9 weeks, passages 1–10) of fibroblasts with IDV, NFV, d4T and ZDV, but not 3TC, decreased the PDL (by four- to fivefold) and the BrdU nuclear staining (by 1.5–2.5-fold) showing that the antiretrovirals (apart from 3TC) had an impact on cell proliferation. This treatment also increased β-galactosidase activity at pH 6 by five- to sevenfold (IDV, NFV) and nine- to tenfold (AZT, d4T) as well as the protein expression of p16INK4 and p21. Fibroblasts progressively acquired a senescent morphology with cell flattening and enlargement with all drugs except 3TC. These data indicate that the antiretrovirals (apart from 3TC) promote premature senescence in human fibroblasts. The PIs (IDV, NFV) and NRTIs (d4T, AZT) also increased ROS production by four- to fivefold. Hyperproduction of ROS was accompanied by a two- to fourfold increase in mitochondrial mass, suggesting mitochondria biogenesis. Mitochondrial potential assessed by JC1 aggregation was not altered by the antiretrovirals.
CONCLUSIONS: PIs and NRTIs known to induce adipocyte dysfunctions in vitro also induced premature cellular senescence in fibroblasts. Whether mitochondrial dysfunction and ROS hyperproduction are the origin or the consequence of senescence remains to be investigated. Premature cell ageing might participate to the lipodystrophy syndrome and the metabolic alterations induced by the antiretrovirals in HIV-infected patients.
Download PDF of this abstract.
2005-11-13
18
Copyright © 2005 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.