来自HIV感染者的单核细胞在跨内皮迁移后表现出胆固醇流出受损和泡沫细胞形成增加。
Monocytes from HIV-infected individuals show impaired cholesterol efflux and increased foam cell formation after transendothelial migration.
作者信息
Maisa Anna, Hearps Anna C, Angelovich Thomas A, Pereira Candida F, Zhou Jingling, Shi Margaret D Y, Palmer Clovis S, Muller William A, Crowe Suzanne M, Jaworowski Anthony
机构信息
aCentre for Biomedical Research, Burnet Institute bDepartment of Infectious Diseases, Monash University cSchool of Applied Sciences, RMIT University dMonash Micro Imaging, Monash University eDepartment of Microbiology and Immunology, Melbourne University, Melbourne, Victoria, Australia fFeinberg School of Medicine, Northwestern University, Chicago, Illinois, USA gDepartment of Immunology, Monash University, Melbourne, Victoria, Australia.
出版信息
AIDS. 2015 Jul 31;29(12):1445-57. doi: 10.1097/QAD.0000000000000739.
DESIGN
HIV-infected (HIV+) individuals have an increased risk of atherosclerosis and cardiovascular disease which is independent of antiretroviral therapy and traditional risk factors. Monocytes play a central role in the development of atherosclerosis, and HIV-related chronic inflammation and monocyte activation may contribute to increased atherosclerosis, but the mechanisms are unknown.
METHODS
Using an in-vitro model of atherosclerotic plaque formation, we measured the transendothelial migration of purified monocytes from age-matched HIV+ and uninfected donors and examined their differentiation into foam cells. Cholesterol efflux and the expression of cholesterol metabolism genes were also assessed.
RESULTS
Monocytes from HIV+ individuals showed increased foam cell formation compared with controls (18.9 vs. 0%, respectively, P = 0.004) and serum from virologically suppressed HIV+ individuals potentiated foam cell formation by monocytes from both uninfected and HIV+ donors. Plasma tumour necrosis factor (TNF) levels were increased in HIV+ vs. control donors (5.9 vs. 3.5 pg/ml, P = 0.02) and foam cell formation was inhibited by blocking antibodies to TNF receptors, suggesting a direct effect on monocyte differentiation to foam cells. Monocytes from virologically suppressed HIV+ donors showed impaired cholesterol efflux and decreased expression of key genes regulating cholesterol metabolism, including the cholesterol transporter ABCA1 (P = 0.02).
CONCLUSION
Monocytes from HIV+ individuals show impaired cholesterol efflux and are primed for foam cell formation following transendothelial migration. Factors present in HIV+ serum, including elevated TNF levels, further enhance foam cell formation. The proatherogenic phenotype of monocytes persists in virologically suppressed HIV+ individuals and may contribute mechanistically to increased atherosclerosis in this population.
设计
感染人类免疫缺陷病毒（HIV）的个体患动脉粥样硬化和心血管疾病的风险增加，这与抗逆转录病毒疗法和传统风险因素无关。单核细胞在动脉粥样硬化的发展中起核心作用，与HIV相关的慢性炎症和单核细胞活化可能导致动脉粥样硬化增加，但其机制尚不清楚。
方法
使用动脉粥样硬化斑块形成的体外模型，我们测量了来自年龄匹配的HIV感染者和未感染供体的纯化单核细胞的跨内皮迁移，并检查了它们向泡沫细胞的分化。还评估了胆固醇流出和胆固醇代谢基因的表达。
结果
与对照组相比，HIV感染者的单核细胞显示出泡沫细胞形成增加（分别为18.9%对0%，P = 0.004），病毒学抑制的HIV感染者的血清增强了未感染和HIV感染者供体的单核细胞的泡沫细胞形成。HIV感染者与对照供体相比，血浆肿瘤坏死因子（TNF）水平升高（5.9对3.5 pg/ml，P = 0.02），并且通过抗TNF受体阻断抗体抑制了泡沫细胞形成，这表明对单核细胞分化为泡沫细胞有直接影响。病毒学抑制的HIV感染者供体的单核细胞显示胆固醇流出受损，调节胆固醇代谢的关键基因表达降低，包括胆固醇转运蛋白ABCA1（P = 0.02）。
结论
HIV感染者的单核细胞显示胆固醇流出受损，并且在跨内皮迁移后易于形成泡沫细胞。HIV感染者血清中存在的因素，包括升高的TNF水平，进一步增强了泡沫细胞形成。单核细胞的促动脉粥样硬化表型在病毒学抑制的HIV感染者中持续存在，并且可能在机制上导致该人群动脉粥样硬化增加。
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