Interventions to Reduce Hypercoagulability in Old SIV-Infected NHPs

降低感染 SIV 的旧 NHP 的高凝状态的干预措施

• 批准号: 9307988
• 负责人: Ivona Vasile Pandrea
• 金额: $ 72.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-07 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307988
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Age; Age-Years; Aging; Alcohols; Anticoagulants; Atherosclerosis; Biological Markers; Blood Coagulation Factor; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Categories; Cause of Death; Cessation of life; Characteristics; Chronic; Clinical; Clinical Management; Coagulation Process; Comorbidity; Consequences of HIV; Data; Development; Diagnostic; Diet; Disease; Disease Progression; Elderly; Embolism; Event; FDA approved; Factor XI; Fibrin fragment D; Fibrosis; HIV; HIV Infections; Hemorrhage; Human; Infection; Inflammation; Inflammatory; Intervention; Knowledge; Link; Lung; Macaca mulatta; Modeling; Monitor; Outcome; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Play; Population; Primates; Reporting; Research; Residual state; Risk; Role; SIV; Severities; Signal Transduction; Smoking; Testing; Therapeutic; Thrombin; Thrombophilia; Thromboplastin; Translational Research; Treatment Efficacy; Treatment Failure; Venous Thrombosis; age related; antiretroviral therapy; antithrombin III-protease complex; base; design; drug efficacy; enhancing factor; experience; experimental study; high risk; immune activation; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; juvenile animal; mortality; nonhuman primate; novel therapeutics; older patient; outcome forecast; prevent; public health relevance; receptor; response; restoration; success; therapeutic target; treatment response

 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.

 描述（由适用提供）：促血栓形成状态是艾滋病毒感染的特征，与心血管（CV）事件和死亡有关。与HIV相关的高凝性的后果在较旧的情况下可能更为严重，即使没有HIV感染，也会受到促血栓性状态的影响。我们报道了非人类灵长类动物（NHP）模型的类似凝血异常，其中D-二聚体（DD）和凝血酶 - 抗凝血酶复合物（TAT）的增加强烈预测了疾病的进展和死亡。我们还表明，与人类类似，NHPS经历了与年龄相关的凝血标志物的增加。 HIV感染的患者与SIV感染的NHP之间存在凝血与免疫激活/炎症（IA/INFRAI​​MANT）之间的密切联系。 inff诱导组织因子（TF）的表达，这是凝血的主要活化剂。反过来，凝血因子通过蛋白质激活剂受体增强炎症信号，保持凝血/浓烈的恶性循环。凝血会触发纤维化，这会阻碍CD4+ T细胞恢复，这可能是艺术失败的原因。这些观察结果以及DD在HIV感染患者和SIV感染的恒河猴（RMS）中表现出强烈的独立死亡风险的发现，表明凝结可能在HIV发病机理中起核心作用，应受到热靶向。我们假设旨在限制较早感染HIV的患者过度凝的干预措施将改善其临床状况对ART的反应。因此，我们将在具有或不使用ART的年轻人与SIVMAC感染的RMS中施用抗凝剂，并评估这些干预措施对凝血状态，IA/INFRIPL，纤维化，CD4+ T细胞恢复，CV合并症和死亡的影响。我们将使用专门针对外在，内在和常见凝血途径的新的和FDA批准的抗凝剂。通过比较和对比这些方法的结果，我们将深入了解与SIV和年龄相关的超凝性的机制，与通常混淆人类研究的因素无关。由于出血和死亡的不明风险，这种体内机械实验无法在HIV感染的患者中，尤其是较旧的患者进行。预计到2015年，美国艾滋病毒感染的患者中有50％> 50岁，非感染并发症的风险将大大增加，并且可能成为治疗慢性HIV感染的主要挑战。因此，我们高度创新的翻译实验解决了我们目前对老年HIV发病机理的知识的主要差距。通过改善对ART的反应并预防CV疾病，这是经过艺术治疗的患者的主要死亡原因，这项研究可能对年龄较大的HIV感染患者的临床管理和存活产生重大影响。