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（由申请人提供）：血栓前状态是 HIV 感染的特征，并且与心血管 (CV) 事件和死亡相关。 HIV 相关的高凝状态的后果在老年人中可能更为严重，老年人受到血栓前状态的影响尤为严重。即使在没有 HIV 感染的情况下，我们也报告了艾滋病的非人类灵长类动物 (NHP) 模型中的类似凝血异常，其中 D-二聚体 (DD) 和我们还发现，与人类相似，NHP 的凝血标记物与年龄相关，凝血标记物与免疫激活/炎症 (IA/INFL) 标记物之间存在密切联系。在 HIV 感染的患者和 SIV 感染的 NHP 中，INFL 会诱导组织因子 (TF) 的表达，而组织因子是凝血的主要激活剂。蛋白酶激活剂受体，维持凝血/INFL 恶性循环 凝血会引发纤维化，从而阻碍 CD4+ T 细胞的恢复，并且可能是 ART 失败的原因。 HIV 感染的患者和 SIV 感染的恒河猴 (RM) 表明凝血可能在 HIV 发病机制中发挥核心作用，并且应该成为治疗的目标。旨在限制老年 HIV 感染患者的高凝状态将改善他们的临床状态，从而改善他们对 ART 的反应，因此，我们将在有或没有 ART 的情况下对年轻和老年 SIVmac 感染 RM 进行抗凝治疗，并评估这些干预措施对凝血状态 IA 的影响。 /INFL、纤维化、CD4+ T 细胞恢复、心血管合并症和死亡 我们将使用 FDA 批准的新型抗凝剂，专门针对外在、内在和常见疾病。通过比较和对比这些方法的结果，我们将深入了解 SIV 和年龄相关的高凝性机制，而不受通常混淆人类研究的因素的影响。由于出血和死亡风险未知，预计到 2015 年，超过 50% 的美国 HIV 感染者年龄将超过 50 岁，因此，非感染性并发症将显着增加，并可能成为慢性艾滋病毒感染管理的主要挑战，因此，我们高度创新的转化实验通过改善抗逆转录病毒疗法的反应和预防，解决了我们目前对老年人艾滋病毒发病机制的了解的主要空白。心血管疾病是接受 ART 治疗的患者死亡的一个主要原因，这项研究可能对老年 HIV 感染患者的临床管理和生存产生重大影响。