HIV 蛋白酶抑制剂不会导致接受一线治疗的患者 PBMC 中前层粘连蛋白 A 的积累：ANRS EP45“衰老”研究。
HIV protease inhibitors do not cause the accumulation of prelamin A in PBMCs from patients receiving first line therapy: the ANRS EP45 "aging" study.
机构信息
Inserm UMR_S 910, Aix-Marseille Université, Marseille, France.
出版信息
PLoS One. 2012;7(12):e53035. doi: 10.1371/journal.pone.0053035. Epub 2012 Dec 28.
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.
背景
ANRS EP45“衰老”研究调查了 HIV-1 感染和治疗患者加速衰老涉及的细胞机制。本报告重点介绍了核纤层蛋白 A 的加工，该途径已知在系统性遗传早衰综合征中发生改变。
方法
35 名接受一线抗逆转录病毒治疗（ART）的 HIV-1 感染患者（包括洛匹那韦/利托那韦[65%的患者]）和 49 名血清阴性、年龄和性别匹配的对照者（http://clinicaltrials.gov/，NCT01038999）被招募。在超过 88%的患者中，病毒载量<40 拷贝/ml，CD4+细胞计数>500/mm³。在纳入时通过蛋白质印迹法分析患者和对照者外周血单个核细胞（PBMC）中的前核纤层蛋白 A 加工。在入组研究后 12 和 24 个月时还对患者的 PBMC 进行了研究。还在含有不同浓度蛋白质（4 至 80 g/L）的培养基中孵育来自健康对照者的 PBMC。
结果
无论使用何种 PI/r、剂量和血浆浓度，队列患者的 PBMC 中均未观察到核纤层蛋白 A 前体。在含有低蛋白浓度（4 g/L）的培养基中孵育的 PBMC 中检测到前核纤层蛋白 A，但在血浆（60-80 g/L）或补充有 BSA（40 g/L）的培养基中均未检测到，两者均含有高浓度的蛋白质。
结论
在接受一线 PI/r 方案治疗的患者的 PBMC 中未观察到前核纤层蛋白 A 加工异常。因此，PI/r 似乎不会导致 PBMC 中与核纤层蛋白 A 相关的衰老。在来自健康供体的培养 PBMC 中，仅当培养基中的蛋白浓度较低时才观察到前核纤层蛋白 A 加工异常，从而增加了进入细胞的 PI 量。ClinicalTrials.gov NCT01038999 http://clinicaltrials.gov/ct2/show/NCT01038999。
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