Hawaii Center for HIV/AIDS, Honolulu, Hawaii, United States of America ; Department of Tropical Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
PLoS One. 2013 Sep 25;8(9):e75500. doi: 10.1371/journal.pone.0075500. eCollection 2013.
Chronic infection by HIV increases the risk of cardiovascular disease (CVD) despite effective antiretroviral therapy (ART). The mechanisms linking HIV to CVD have yet to be fully elucidated. High plasma levels of the pro-inflammatory cytokine IL-6, which may be triggered by IL-1β, is a biomarker of CVD risk in HIV-negative adults, and of all-cause mortality in HIV disease. Monocytes play a pivotal role in atherosclerosis, and may be major mediators of HIV-associated inflammation. We therefore hypothesized that monocytes from HIV-infected adults would display high inflammatory responses. Employing a 10-color flow cytometry intracellular cytokine staining assay, we directly assessed cytokine and chemokine responses of monocytes from the cryopreserved peripheral blood of 33 chronically HIV-1 infected subjects. Participants were 45 years or older, on virologically suppressive ART and at risk for CVD. This group was compared to 14 HIV-negative subjects matched for age and gender, with similar CVD risk. We simultaneously detected intracellular expression of IL-1β, IL-6, IL-8 and TNF in blood monocytes in the basal state and after stimulation by triggers commonly found in the blood of treated, chronically HIV-infected subjects: lipopolysaccharide (LPS) and oxidized low-density lipoprotein (oxLDL). In the absence of stimulation, monocytes from treated HIV-infected subjects displayed a high frequency of cells producing IL-1β (median 19.5%), compared to low levels in HIV-uninfected persons (0.9% p<0.0001). IL-8, which is induced by IL-1β, was also highly expressed in the HIV-infected group in the absence of stimulation, 43.7% compared to 1.9% in HIV-uninfected subjects, p<0.0001. Strikingly, high basal expression of IL-1β by monocytes predicted high IL-6 levels in the plasma, and high monocyte IL-6 responses in HIV-infected subjects. Hyper-inflammatory IL-1β enriched monocytes may be a major source of IL-6 production and systemic inflammation in HIV-infected adults, and may contribute to the risk for all-cause mortality and cardiovascular disease in treated HIV infection.
慢性 HIV 感染会增加心血管疾病（CVD）的风险，尽管有有效的抗逆转录病毒治疗（ART）。将 HIV 与 CVD 联系起来的机制尚未完全阐明。高水平的促炎细胞因子 IL-6 可能由 IL-1β 触发，这是 HIV 阴性成年人 CVD 风险的生物标志物，也是 HIV 疾病全因死亡率的生物标志物。单核细胞在动脉粥样硬化中起关键作用，并且可能是与 HIV 相关炎症的主要介质。因此，我们假设 HIV 感染的成年人的单核细胞会表现出高度的炎症反应。我们采用 10 色流式细胞术细胞内细胞因子染色测定法，直接评估了 33 名慢性 HIV-1 感染患者冷冻保存外周血单核细胞的细胞因子和趋化因子反应。参与者年龄在 45 岁或以上，接受病毒学抑制性 ART 治疗，且存在 CVD 风险。将该组与 14 名年龄和性别匹配的 HIV 阴性受试者进行比较，这些受试者具有相似的 CVD 风险。我们同时检测了在治疗慢性 HIV 感染患者血液中常见的刺激物（脂多糖（LPS）和氧化低密度脂蛋白（oxLDL）刺激下，血液单核细胞中内源性表达的 IL-1β、IL-6、IL-8 和 TNF。在没有刺激的情况下，与 HIV 未感染的个体（0.9%，p<0.0001）相比，接受治疗的 HIV 感染患者的单核细胞产生 IL-1β 的细胞频率较高（中位数 19.5%）。IL-8 是由 IL-1β 诱导的，在没有刺激的情况下，HIV 感染组的表达也很高，为 43.7%，而 HIV 未感染组为 1.9%，p<0.0001。令人惊讶的是，单核细胞中 IL-1β 的基础高表达预测了 HIV 感染患者血浆中 IL-6 水平升高，以及 HIV 感染患者中单核细胞 IL-6 反应升高。高炎症性 IL-1β 富集单核细胞可能是 HIV 感染成年人中 IL-6 产生和全身炎症的主要来源，并可能导致治疗性 HIV 感染的全因死亡率和心血管疾病风险增加。
