Impact of NETosis on SIV Pathogenesis and Response to Treatment

NETosis 对 SIV 发病机制和治疗反应的影响

• 批准号: 10402152
• 负责人: Ivona Vasile Pandrea
• 金额: $ 78.13万
• 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: 2015-07-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10402152
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adjuvant; Age; Animal Model; Automobile Driving; Biological Markers; Blood Platelets; CD4 Positive T Lymphocytes; COVID-19; Cardiovascular Diseases; Cause of Death; Cells; Cessation of life; Chronic; Clinical Management; Coagulation Process; Data; Development; Disease; Disease Progression; Environment; Fibrin fragment D; Frequencies; Functional disorder; Goals; HIV; HIV Infections; Immune; Individual; Infection; Inflammation; Inflammatory; Intervention; Intestines; Knowledge; Laboratories; Macaca; Macaca nemestrina; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Natural History; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Platelet Count measurement; Population; Process; Production; Prognosis; Recovery; Reporting; Research; Residual state; Role; SIV; Testing; Thrombophilia; Thromboplastin; Thrombosis; Tissues; Virus; Virus Replication; antiretroviral therapy; antithrombin III-protease complex; base; chronic infection; comorbidity; cytokine; design; experimental study; extracellular; gut health; immune activation; improved; in vivo; inhibitor; innovation; mortality; neutrophil; nonhuman primate; novel therapeutics; pandemic disease; response; restoration; therapy development; treatment response

Antiretroviral therapy (ART) has dramatically changed the landscape of chronic HIV infection and massively reduced mortality in persons living with HIV (PWH). Yet, many PWH present with intestinal dysfunction, residual immune activation and inflammation, incomplete immune restoration and a hypercoagulable state, all of which drive a poor prognosis and development of non-AIDS comorbidities, such as the cardiovascular disease (CVD). The pathways involved in the development of CVD in PWH and SIV-infected macaques are not completely elucidated. We recently reported that neutrophil dysfunction may be a key driver of this process, through overwhelming activation and excessive production of neutrophil extracellular traps (NETs). By studying the dynamics and functions of NETs in SIV infection, we showed that they may contribute to disease progression and comorbidities: (a) proinflammatory NETosis increases throughout untreated SIV infection, and is only partially reduced by ART, (b) NETs may be a determinant of the indiscriminate depletion of immune cells that are not virus targets, and of the incomplete CD4+ T cell restoration observed in PWH on ART, and (c) NETosis may promote thrombosis in the thrombocytopenic environment of HIV/SIV infections by capturing platelets and expressing tissue factor. We thus propose a project to assess the role of NETosis in HIV disease progression and response to ART through a direct intervention in vivo. We will use an SIVsab/PTM model developed in our laboratory that faithfully reproduce both key aspects of SIV pathogenesis on ART and the CV disease. We will also use a NET inhibitor that has been validated in vivo by numerous studies in murine animal models. In preliminary studies, we demonstrated that this drug has the ability to inhibit ex vivo production of NETs by neutrophils isolated from our SIV-infected PTMs. We will first test the hypothesis that NETosis is involved in driving SIV pathogenesis and disease progression. To this goal, we will administer the NET inhibitor during chronic infection to untreated SIV-infected PTMs and assess its impact on the natural history of SIV infection, including CV comorbidities. These experiments are designed to model those PWH who either do not receive ART or do not achieve complete virus suppression on ART. Second, we will test the hypothesis that NETosis is involved in driving the response to ART and development of CV comorbidities. To this goal, we will administer a NET inhibitor to ART-treated SIV-infected PTMs and assess the consequences of this intervention on the CD4+ T cell restoration, inflammation, coagulation and CV disease development. These experiments are designed to model PWH, who receive ART. This highly innovative project will improve our understanding of HIV pathogenesis and mechanisms of HIV-related comorbidities, particularly the CVD, a major cause of death in PWH, and thus may have a critical impact on the clinical management and survival of the PWH.

抗逆转录病毒疗法（ART）急剧改变了慢性HIV感染的景观和大规模的景观 患有艾滋病毒（PWH）的人死亡率降低。然而，许多PWH存在肠功能障碍，残留 免疫激活和炎症，不完整的免疫恢复和超凝状态，所有这些状态 推动了非AIDS合并症（例如心血管疾病（CVD））的不良预后和发展。 PWH和SIV感染的猕猴在CVD开发中涉及的途径并不完全 阐明。我们最近报告说，中性粒细胞功能障碍可能是此过程的关键驱动力 大量的激活和中性粒细胞外陷阱的过度产生（网）。通过研究 我们表明它们可能有助于疾病进展 和合并症：（a）促炎性肠病在未经治疗的SIV感染中增加，仅是 （b）部分降低了ART的部分减少，可能是免疫细胞不分青红皂白的耗尽的决定因素 不是病毒靶标，也不是ART PWH中观察到的不完整的CD4+ T细胞恢复，（C）Netosis 可以通过捕获血小板和 表达组织因子。因此，我们提出了一个评估Netosis在HIV疾病进展中的作用的项目 通过直接干预体内对艺术的反应。我们将使用在我们的 忠实地重现ART和CV疾病的SIV发病机理的两个关键方面的实验室。我们将 还使用鼠模型中的许多研究对体内验证的净抑制剂。在 初步研究，我们证明了这种药物具有抑制网络产生网的能力 从我们的SIV感染的PTM中分离出的中性粒细胞。我们将首先检验Netosis参与的假设 驱动SIV发病机理和疾病进展。为了实现这一目标，我们将管理净抑制剂 长期感染未处理的SIV感染的PTM，并评估其对SIV感染自然史的影响， 包括简历合并症。这些实验旨在建模那些未收到的PWH 艺术或不能在艺术上获得完全抑制病毒。其次，我们将检验Netosis的假设 参与推动对简历合并症的艺术和发展的反应。为了实现这一目标，我们将 将净抑制剂纳入经ART处理的SIV感染的PTM，并评估此干预的后果 在CD4+ T细胞恢复，炎症，凝结和CV疾病发展上。这些实验是 旨在建模PWH，谁获得艺术。这个高度创新的项目将改善我们对艾滋病毒的理解 HIV相关合并症的发病机理和机制，尤其是CVD，这是主要的死亡原因 PWH，因此可能对PWH的临床管理和生存产生关键影响。