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. 2012;7(12):e53035. doi: 10.1371/journal.pone.0053035. Epub 2012 Dec 28.

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. ClinicalTrials.gov NCT01038999 http://clinicaltrials.gov/ct2/show/NCT01038999.

Publication types

  • Controlled Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects*
  • Aging / metabolism
  • Atazanavir Sulfate
  • Carbamates / pharmacology
  • Carbamates / therapeutic use
  • Cross-Sectional Studies
  • Female
  • Furans
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / metabolism
  • HIV Infections / physiopathology
  • HIV Protease Inhibitors / pharmacology*
  • HIV Protease Inhibitors / therapeutic use
  • Humans
  • Lamin Type A
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / metabolism*
  • Leukocytes, Mononuclear / virology
  • Longitudinal Studies
  • Lopinavir / pharmacology
  • Lopinavir / therapeutic use
  • Male
  • Nuclear Proteins / metabolism*
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Protein Precursors / metabolism*
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Ritonavir / pharmacology
  • Ritonavir / therapeutic use
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Viral Load

Substances

  • Carbamates
  • Furans
  • HIV Protease Inhibitors
  • Lamin Type A
  • Nuclear Proteins
  • Oligopeptides
  • Protein Precursors
  • Pyridines
  • Sulfonamides
  • prelamin A
  • Lopinavir
  • Atazanavir Sulfate
  • amprenavir
  • Ritonavir

Associated data

  • ClinicalTrials.gov/NCT01038999

Grant support

This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, http://www.anrs.fr/) [ANRS EP45 “Aging” to PC]. SP was a recipient of a 3-year PhD grant from ANRS [ANRS EP45 “Aging” to PC] and an additional one-year PhD grant from Sidaction (http://www.sidaction.org/) [B/22-2-02032 to SP]. SP received a 3-month transition grant from ADEREM (Biological and medical research supportive association for Marseille hospital centres, http://aderem.fr/index.htm). JC was a recipient of a grant from Sidaction [A/19-3-01487 to PC]. PC was a recipient of grants from GlaxoSmithKline and from Boehringer Mannheim. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.