Interventions to Reduce Hypercoagulability in Old SIV-Infected NHPs

 描述(由申请人提供)：血栓前状态是艾滋病毒感染的特征，与心血管事件和死亡有关。艾滋病毒相关高凝状态的后果在老年人中可能更为严重，即使在没有感染艾滋病毒的情况下，老年人也会不成比例地受到血栓前状态的影响。我们报道了在非人灵长类动物(NHP)艾滋病模型中类似的凝血异常，在这些模型中，D-二聚体(DD)和凝血酶-抗凝血酶复合体(TAT)的增加强烈地预测了疾病的进展和死亡。我们还表明，与人类相似，NHP经历了与年龄相关的凝血标志物的增加。在HIV感染患者和SIV感染的NHP中，凝血和免疫激活/炎症(IA/INFL)标志物之间存在着强烈的联系。Inf1诱导凝血的主要激活物组织因子(TF)的表达。反过来，凝血因子通过蛋白酶-激活物受体增强炎症信号，维持凝血/凝血恶性循环。凝血引发纤维化，这阻碍了CD4+T细胞的恢复，可能是ART失败的原因之一。这些观察结果，再加上DD在HIV感染患者和SIV感染猕猴(RMS)中都显示出强烈的独立死亡风险，表明凝血可能在HIV发病机制中发挥核心作用，应作为治疗靶点。我们假设，旨在限制老年HIV感染患者高凝状态的干预措施将改善他们的临床状态，这是对ART的反应。因此，我们将在年轻和老年感染SIVmac的RMS中使用抗凝剂，无论是否使用ART，并评估这些干预措施对凝血状态、IA/INFL、纤维化、CD4+T细胞恢复、心血管并发症和死亡的影响。我们将使用FDA批准的新型抗凝剂，专门针对外源性、内源性和常见的凝血途径。通过比较和对比这些方法的结果，我们将深入了解SIV和年龄相关的高凝状态的机制，独立于通常混淆人类研究的因素。由于出血和死亡的风险未知，这种体内机制实验不能在艾滋病毒感染患者身上进行，特别是在老年患者身上。由于预计到2015年，美国50%的艾滋病毒感染者将达到50岁，非传染性并发症的风险将显著增加，并可能成为慢性艾滋病毒感染管理的主要挑战。因此，我们的高度创新的翻译实验解决了我们目前对老年人艾滋病毒发病机制的主要认识空白。通过改善对抗逆转录病毒治疗的反应和预防心血管疾病，这是接受抗逆转录病毒治疗患者的主要死亡原因，这项研究可能对老年艾滋病毒感染患者的临床管理和生存产生重大影响。

 DESCRIPTION (provided by applicant): A prothrombotic status is characteristic to HIV infection, and is associated with cardiovascular (CV) events and death. The consequences of HIV-related hypercoagulability may be even more severe in elderly, which are disproportionally affected by a prothrombotic status even in the absence of HIV infection. We reported similar coagulation abnormalities in nonhuman primate (NHP) models of AIDS in which increases of D-Dimer (DD) and thrombin-antithrombin complex (TAT) strongly predict disease progression and death. We also showed that, similar to humans, NHPs experience age-related increases of coagulation markers. A strong connection between coagulation and immune activation/inflammation (IA/INFL) markers exists in HIV- infected patients and SIV-infected NHPs. INFL induces expression of tissue factor (TF), a major activator of coagulation. In turn, coagulation factors enhance inflammatory signals via protease-activator receptors, maintaining a coagulation/INFL vicious cycle. Coagulation triggers fibrosis, which impedes CD4+ T cell restoration and may be a reason for ART failure. These observations, together with the finding that DD shows a strong independent risk for mortality in both HIV-infected patients and SIV-infected rhesus macaques (RMs), suggest that coagulation may play a central role in HIV pathogenesis and should be therapeutically targeted. We hypothesize that interventions aimed at limiting hypercoagulation in elderly HIV-infected patients will improve their clinical status an response to ART. We will therefore administer anticoagulants in young vs. older SIVmac-infected RMs with or without ART and assess the impact of these interventions on coagulation status, IA/INFL, fibrosis, CD4+ T cell restoration, CV comorbidities and death. We will use new and FDA- approved anticoagulants specifically targeting the extrinsic, intrinsic and common coagulation pathways. By comparing and contrasting the results of these approaches, we will gain insight into the mechanisms of SIV- and age-related hypercoagulability, independent of factors that usually confound human studies. Such in vivo mechanistic experiments cannot be performed in HIV-infected patients, particularly in older ones, due to the unknown risk of hemorrhages and death. With >50% of the US HIV-infected patients anticipated to be >50 years of age by 2015, the risk of noninfectious complications will be significantly higher and could become the main challenge for the management of chronic HIV infection. As such, our highly innovative, translational experiments address major gaps in our current knowledge of HIV pathogenesis in elderly. By improving the response to ART and preventing CV disease, a major cause of death in ART-treated patients, this research may have a major impact for the clinical management and survival of elderly HIV-infected patients.