HIV-1, Exercise and Endothelial Function

描述(申请人提供)：心血管疾病(CVD)是人类免疫缺陷病毒(HIV)-1感染的成年人中出现的一个新问题，包括那些接受抗逆转录病毒治疗(ART)的人。前瞻性和回顾性研究表明，与HIV-1血清阴性者相比，接受抗逆转录病毒治疗的HIV-1感染者患动脉粥样硬化和心肌梗死的风险更高。在HIV-1感染人群中，与加速的动脉粥样硬化相关的大部分风险与传统的风险因素无关，其背后的机制尚未完全了解。此外，还没有建立有效的非药物干预策略来预防和/或降低接受抗逆转录病毒治疗的HIV-1感染成人动脉粥样硬化性血管疾病的风险。越来越多的证据表明，接受抗逆转录病毒治疗的HIV-1感染者具有致动脉粥样硬化的内皮细胞表型，其特征是血管运动和纤溶调节受损。有规律的有氧运动被广泛认为是对心血管疾病的一级和二级预防最有效的非药物干预。到目前为止，关于有氧运动对HIV-1血清阳性成年人的影响的研究主要集中在心肺和代谢适应上。目前尚不清楚有氧运动训练是否能改善接受抗逆转录病毒治疗的HIV-1感染者的内皮功能。因此，本提案的具体目标1和2将确定定期有氧运动计划是否改善：1)血管内皮依赖的一氧化氮介导的血管扩张；以及2)先前久坐不动的HIV-1感染的成年人在接受抗逆转录病毒治疗时，血管内皮细胞释放组织型纤溶酶原激活剂(t-PA)的能力。具体目标3将确定，在接受抗逆转录病毒治疗的HIV-1感染者中，运动诱导的内皮血管扩张剂和纤溶功能的增加是否至少部分归因于减少氧化应激和炎症。为了达到这些目标，将对80名HIV-1血清阳性成年人进行研究，这些成年人年龄从30岁到50岁不等，接受他们的第一个ART方案，包括替诺福韦和恩曲他滨联合法韦伦或阿扎那韦和利托那韦。受试者将被随机分配到有氧运动训练组或注意力控制组，为期24周。在24周的干预期之前和之后，将使用隔离的前臂模型来确定内皮依赖性血管扩张、内皮t-PA释放以及氧化应激对每个功能特征的影响。本研究的结果将提供对HIV-1感染者加速的动脉粥样硬化的机械性洞察，并支持使用定期有氧运动作为辅助治疗，以减少和预防这一高度易感人群的心血管疾病。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is an emerging problem in human immunodeficiency virus (HIV)-1-infected adults, including those treated with antiretroviral therapy (ART). Prospective and retrospective studies have indicated that HIV-1-infected individuals on ART are at increased risk of atherosclerosis and myocardial infarction compared with HIV-1-seronegative individuals. Much of the risk associated with accelerated atherosclerosis in the HIV-1-infected population is independent of traditional risk factors, and the mechanisms underlying this are not completely understood. Furthermore, effective non-pharmacological intervention strategies to prevent and/or reduce the risk of atherosclerotic vascular disease in HIV-1-infected adults receiving ART have not been established. There is increasing evidence that ART-treated HIV-1-infected individuals have a proatherogenic endothelial phenotype characterized by impaired vasomotor and fibrinolytic regulation. Regular aerobic exercise is widely regarded as the most effective non-pharmacological intervention for both primary and secondary prevention of CVD. To date, studies on the effects of aerobic exercise training in HIV-1-seropositive adults have focused on cardiorespiratory and metabolic adaptations. It is currently unknown whether aerobic exercise training can improve endothelial function in HIV-1-infected adults receiving ART. Accordingly, specific aims 1 and 2 of the present proposal will be to determine if a program of regular aerobic exercise improves: 1) vascular endothelium-dependent nitric oxide-mediated vasodilation; and 2) the capacity of the vascular endothelium to release tissue-type plasminogen activator (t-PA) in previously sedentary HIV-1-infected adults without traditional cardiometabolic risk factors for coronary artery disease who are receiving antiretroviral therapy. Specific aim 3 will determine if the exercise-induced increase in endothelial vasodilator and fibrinolytic function in HIV-1-infected adults receiving antiretroviral therapy is due, at least in part, to reduced oxidative stress and inflammation. To address these aims, 80 HIV-1-seropositive adults, ranging in age from 30-50 years, receiving their first ART regimen consisting of tenofovir and emtricitabine combined with either efavirenz or atazanavir boosted with ritonavir will be studied. Subjects will be randomly assigned to either an aerobic exercise training group or an attention control group for 24 weeks. Endothelium- dependent vasodilation, endothelial t-PA release and the effects of oxidative stress on each functional characteristic will be determined before and after the 24-week intervention period using an isolated forearm model. The results of the present study will provide mechanistic insight into the accelerated atherosclerosis seen in HIV-1-infected individuals and support use of regular aerobic exercise as adjunctive therapy to reduce and prevent cardiovascular disease in this highly susceptible population.