Abstract
BackgroundThe 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.Methods35 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).ResultsLamin 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.ConclusionsPrelamin 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.
Highlights
The A-type lamins are type V intermediate filaments that are key components of the nuclear matrix
The cysteine residue in the C-terminal CaaX box is farnesylated in the first step [5], following which the aaX residues are removed by the endopeptidases, FACE1/ZMPSTE24 and/or FACE2/RCE1 [6]
The present study focused on prelamin A in peripheral blood mononuclear cells (PBMCs) from 35 HIV-1 infected patients treated with first line antiretroviral therapy (ART) comprising 2NRTI+1PI/r
Summary
The A-type lamins are type V intermediate filaments that are key components of the nuclear matrix. Lamin C is produced directly as a mature protein, while lamins A undergo several posttranslational modifications [2,3,4]. Mature proteins are obtained from their precursors through 4 posttranslational steps. The cysteine is subsequently carboxymethylated by ICMT (isoprenylcysteine carboxyl methyltransferase) [6]. Following this step, the last 15 C-terminal amino acids of prelamin A are cleaved by FACE1/ZMPSTE24 to release a mature unfarnesylated soluble protein present in both the lamina and in the rest of the nucleoplasm [7,8]. The present report focuses on lamin A processing, a pathway known to be altered in systemic genetic progeroid syndromes
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