HIV-1 Infection and First Line ART Induced Differential Responses in Mitochondria from Blood Lymphocytes and Monocytes: The ANRS EP45 “Aging” Study

Sophie Perrin 1, 2 Jonathan Cremer 1, 2 Patrice Roll 1, 2 Olivia Faucher 3 Amélie Menard 3 Jacques Reynes 4 Pierre Dellamonica 5 Alissa Naqvi 5 Joëlle Micallef 6 Elisabeth Jouve 6 Catherine Tamalet 7, 8 Caroline Solas 9, 10 Christel Pissier 9, 10 Isabelle Arnoux 11 Corine Nicolino-Brunet 12 Leon Espinosa 8 Nicolas Lévy 1, 13 Elise Kaspi 1, 2 Andrée Robaglia-Schlupp 1, 2 Isabelle Poizot-Martin 3 Pierre Cau 1, 2
1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM]
APHM - Assistance Publique - Hôpitaux de Marseille, TIMONE - Hôpital de la Timone [CHU - APHM]
3 Service d'Immuno-hématologie clinique [Hôpital Sainte Marguerite - APHM]
4 TransVIHMI - Recherches Translationnelles sur le VIH et les maladies infectieuses
5 Service de Maladies Infectieuses [Nice]
6 CIC - Centre d'Investigation Clinique [Hôpital de la Conception - APHM]
7 Fédération de Microbiologie Clinique
8 URMITE - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes
9 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
10 Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM]
11 Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM]
12 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
13 Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM]
Département de génétique médicale [Hôpital de la Timone - APHM]
Abstract : Background: The ANRS EP45 “Aging” study investigates the cellular mechanisms involved in the accelerated aging of HIV-1 infected and treated patients. The data reported focus on mitochondria, organelles known to be involved in cell senescence. Methods: 49 HIV-1 infected patients untreated with antiretroviral therapy, together with 49 seronegative age- and sex-matched control subjects and 81 HIV-1 infected and treated patients, were recruited by 3 AIDS centres (Marseille, Montpellier, Nice; France; http://clinicaltrials.gov/, NCT01038999). In more than 88% of treated patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm3. ROS (reactive oxygen species) production and ΔΨm (inner membrane potential) were measured by flow cytometry in blood lymphocytes and monocytes (functional parameters). Three mitochondrial network quantitative morphological parameters were computed using confocal microscopy and image analysis. Three PBMC mitochondrial proteins (porin and subunits 2 and 4 of cytochrome C oxidase encoded by mtDNA or nuclear DNA, respectively) were analysed by western blotting. Results: Quantitative changes in PBMC mitochondrial proteins were not induced by either HIV-1 infection or ART. Discriminant analysis integrating functional (ROS production and ΔΨm) or morphological (network volume density, fragmentation and branching) parameters revealed HIV-1 infection and ART differential effects according to cell type. First line ART tended to rescue lymphocyte mitochondrial parameters altered by viral infection, but induced slight changes in monocytes. No statistical difference was found between the effects of three ART regimens on mitochondrial parameters. Correlations between functional parameters and viral load confirmed the damaging effects of HIV-1 in lymphocyte mitochondria. Conclusions: In patients considered to be clinically stable, mitochondria exhibited functional and morphological modifications in PBMCs resulting from either direct or indirect effects of HIV-1 infection (lymphocytes), or from first line ART (monocytes). Together with other tissue impairments, these changes may contribute to global aging.
Keywords : Lymphocytes Mitochondria Apoptosis T cells Monocytes HIV-1 Antiretroviral therapy Viral load
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UNIV-AMU | IRD | MMG | BS | UNIV-MONTPELLIER

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Sophie Perrin, Jonathan Cremer, Patrice Roll, Olivia Faucher, Amélie Menard, et al.. HIV-1 Infection and First Line ART Induced Differential Responses in Mitochondria from Blood Lymphocytes and Monocytes: The ANRS EP45 “Aging” Study. PLoS ONE, Public Library of Science, 2012, 7 (7), pp.e41129. 〈http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041129〉. 〈10.1371/journal.pone.0041129〉. 〈hal-01646453〉

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