Brites-Alves Clara, Luz Estela, Netto Eduardo M, Ferreira Thalis, Diaz Ricardo Sohbie, Pedroso Celia, Page Kimberly, Brites Carlos
LAPI - Laboratório de Pesquisa em Infectologia, Complexo Hospitalar Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, Brazil.
Laboratório de Retrovirologia, Universidade Federal de São Paulo, São Paulo, Brazil.
Front Immunol. 2018 Jun 26;9:1469. doi: 10.3389/fimmu.2018.01469. eCollection 2018.
Cardiovascular events (CVE) are an increasing cause of morbi-mortality for HIV patients. The antiretroviral therapy (ART), persistent immune activation, and life style are factors that can increase CVE for such patients. We performed a case-control study to evaluate the role of coinfections and immune markers associated with CVE.
We included patients under ART, with undetectable plasma viral load ≥12 months. Patients presenting any condition of risk for CVE were considered cases, and those without CVE risk conditions were controls. History of viral infections (Epstein-Barr virus, hepatitis C virus, hepatitis B virus, and cytomegalovirus), exposure to antiretroviral drugs, time since HIV diagnosis/under ART, and life style (demographics, weight, smoking, alcohol, and illicit drug use) were assessed. CD4/CD8 nadir and current counts, nadir and current CD4/CD8 ratio, immune activation markers (CD4CD38HLADR, CD8CD38HLADR), and serum levels of eight cytokines [IL-2, IL-4, IL-6, IL-10, tumoral necrosis factor-alpha (TNF-α), interferon gamma, macrophage inflammatory proteins 1 alpha, and interferon-inducing protein (IP-10)] were measured.
Two-thirds of patients were males. Cases ( = 106) were older (52.8 vs 49.5 years, = 0.002), had higher levels of creatinine (0.97 vs 0.87 mg/dL, = 0.002) and IL-6 (0.67 vs 0.52 pg/mL, = 0.04) than controls ( = 114). There was no difference between groups regarding frequency of CD4CD39HLADR+ or CD8CD38HLADR+ cells. We found a significant correlation (all patients) between increased frequency of CD4CD38HLADR+ cells and levels of IP-10 ( = 0.171, = 0.02) and TNF-α ( = 0.187, = 0.01). Levels of IL-6 ( = 0.235, = 0.02), TNF-α ( = 0.267, = 0.01), and IP-10 ( = 0.205, = 0.04) were correlated with CD4CD38HLADR+ cells, in controls. Higher frequency of CD4CD38HLADR+ cells was also correlated with levels of IP-10 ( = 0.271, = 0.04) in patients presenting with arterial hypertension. Frequency of CD4CD38HLADR+ cells was negatively correlated with levels of IL-2 ( = -0.639, = 0.01) and IL-6 ( = -0.0561, = 0.03) in patients with hypercholesterolemia. No association was detected between viral infections or smoking/alcohol use and immune activation markers.
Our results indicate IL-6 levels are associated with increased CV risk. Activated CD4+ T cells were associated with increased levels of proinflammatory cytokines.
心血管事件（CVE）是导致HIV患者发病和死亡的一个日益重要的原因。抗逆转录病毒疗法（ART）、持续的免疫激活和生活方式是可增加此类患者发生CVE风险的因素。我们开展了一项病例对照研究，以评估合并感染及与CVE相关的免疫标志物的作用。
我们纳入了接受ART治疗且血浆病毒载量持续至少12个月检测不到的患者。有任何CVE风险状况的患者被视为病例组，而无CVE风险状况的患者为对照组。评估病毒感染史（爱泼斯坦-巴尔病毒、丙型肝炎病毒、乙型肝炎病毒和巨细胞病毒）、抗逆转录病毒药物暴露情况、自HIV诊断/接受ART治疗以来的时间以及生活方式（人口统计学特征、体重、吸烟、饮酒和使用非法药物）。检测CD4/CD8最低点及当前计数、最低点及当前CD4/CD8比值、免疫激活标志物（CD4CD38HLADR、CD8CD38HLADR）以及8种细胞因子的血清水平[白细胞介素-2（IL-2）、白细胞介素-4（IL-4）、白细胞介素-6（IL-6）、白细胞介素-10、肿瘤坏死因子-α（TNF-α）、干扰素-γ、巨噬细胞炎性蛋白1α和干扰素诱导蛋白（IP-10）]。
三分之二的患者为男性。病例组（n = 106）年龄更大（52.8岁对49.5岁，P = 0.002），肌酐水平（0.97mg/dL对0.87mg/dL，P = 0.002）和IL-6水平（0.67pg/mL对0.52pg/mL，P = 0.04）高于对照组（n = 114）。两组间CD4CD39HLADR+或CD8CD38HLADR+细胞频率无差异。我们发现（所有患者中）CD4CD38HLADR+细胞频率增加与IP-10水平（r = 0.171，P = 0.02）和TNF-α水平（r = 0.187，P = 0.01）之间存在显著相关性。在对照组中，IL-6水平（r = 0.235，P = 0.02）、TNF-α水平（r = 0.267，P = 0.01）和IP-10水平（r = 0.205，P = 0.04）与CD4CD38HLADR+细胞相关。在患有动脉高血压的患者中，较高频率的CD4CD38HLADR+细胞也与IP-10水平（r = 0.271，P = 0.04）相关。在患有高胆固醇血症的患者中，CD4CD38HLADR+细胞频率与IL-2水平（r = -0.639，P = 0.01）和IL-6水平（r = -0.0561，P = 0.03）呈负相关。未检测到病毒感染或吸烟/饮酒与免疫激活标志物之间存在关联。
我们的结果表明IL-6水平与心血管风险增加相关。活化的CD4+ T细胞与促炎细胞因子水平升高相关。
