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HIV Protease Inhibitors Do Not Cause the Accumulation of Prelamin A in PBMCs from Patients Receiving First Line Therapy: The ANRS EP45 “Aging” Study

Sophie Perrin 1, 2 Jonathan Cremer 1, 2 Olivia Faucher 3 Jacques Reynes 4 Pierre Dellamonica 5 Joëlle Micallef 6 Caroline Solas 7, 8 Bruno Lacarelle 8, 7 Charlotte Stretti 1, 2 Elise Kaspi 1, 2 Andrée Robaglia-Schlupp 2, 1, 9 Corine Nicolino-Brunet 10 Catherine Tamalet 11, 12 Nicolas Lévy 1, 13 Isabelle Poizot-Martin 3 Pierre Cau 2, 1 Patrice Roll 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 des maladies infectieuses
6 CIC - Centre d'Investigation Clinique [Hôpital de la Conception - APHM]
7 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
8 Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM]
9 TIMONE - Hôpital de la Timone [CHU - APHM]
10 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
11 Fédération de Microbiologie Clinique
12 URMITE - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes
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 present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes. Methods: 35 HIV-1 infected patients being treated with first line antiretroviral therapy (ART, mean duration at inclusion: 2.7±1.3 years) containing boosted protease inhibitors (PI/r) (comprising lopinavir/ritonavir in 65% of patients) were recruited together with 49 seronegative age- and sex-matched control subjects (http://clinicaltrials.gov/, NCT01038999). In more than 88% of patients, the viral load was <40 copies/ml and the CD4+ cell count was >500/mm3. Prelamin A processing in peripheral blood mononuclear cells (PBMCs) from patients and controls was analysed by western blotting at inclusion. PBMCs from patients were also investigated at 12 and 24 months after enrolment in the study. PBMCs from healthy controls were also incubated with boosted lopinavir in culture medium containing various concentrations of proteins (4 to 80 g/L). Results: Lamin A precursor was not observed in cohort patient PBMC regardless of the PI/r used, the dose and the plasma concentration. Prelamin A was detected in PBMC incubated in culture medium containing a low protein concentration (4 g/L) but not in plasma (60–80 g/L) or in medium supplemented with BSA (40 g/L), both of which contain a high protein concentration. Conclusions: Prelamin A processing abnormalities were not observed in PBMCs from patients under the PI/r first line regimen. Therefore, PI/r do not appear to contribute to lamin A-related aging in PBMCs. In cultured PBMCs from healthy donors, prelamin A processing abnormalities were only observed when the protein concentration in the culture medium was low, thus increasing the amount of PI available to enter cells.
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Sophie Perrin, Jonathan Cremer, Olivia Faucher, Jacques Reynes, Pierre Dellamonica, et al.. HIV Protease Inhibitors Do Not Cause the Accumulation of Prelamin A in PBMCs from Patients Receiving First Line Therapy: The ANRS EP45 “Aging” Study. PLoS ONE, Public Library of Science, 2012, 7 (12), pp.e53035. ⟨10.1371/journal.pone.0053035⟩. ⟨hal-01646470⟩

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