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

基本信息

批准号：
10666361
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
项目类别：
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/10666361
关键词：
Acceleration 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 Experimental Designs Fibrin fragment D Frequencies Functional disorder Goals HIV HIV Infections HIV/AIDS 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 chronic infection comorbidity cytokine design experimental study extracellular gut health immune activation improved in vivo inhibitor innovation mortality neutrophil nonhuman primate novel therapeutics pandemic potential response restoration treatment response

项目摘要

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) 极大地改变了慢性 HIV 感染的状况，并极大地降低艾滋病毒感染者（PWH）的死亡率。然而，许多感染者出现肠道功能障碍、残留免疫激活和炎症、免疫恢复不完全和高凝状态，所有这些导致不良预后和非艾滋病合并症的发展，例如心血管疾病（CVD）。感染 PWH 和 SIV 的猕猴发生 CVD 的途径尚不完全清楚阐明了。我们最近报道，中性粒细胞功能障碍可能是这一过程的关键驱动因素，通过中性粒细胞胞外陷阱（NET）的压倒性激活和过量产生。通过研究 NETs 在 SIV 感染中的动态和功能，我们表明它们可能有助于疾病进展和合并症：(a) 促炎性 NETosis 在未经治疗的 SIV 感染期间增加，并且仅 ART 部分减少，(b) NET 可能是免疫细胞不加区别地耗竭的决定因素，不是病毒靶标，并且在接受 ART 的 PWH 中观察到 CD4+ T 细胞恢复不完全，以及 (c) NETosis 可能通过捕获血小板和促进 HIV/SIV 感染的血小板减少环境中的血栓形成表达组织因子。因此，我们提出了一个项目来评估 NETosis 在 HIV 疾病进展中的作用以及通过体内直接干预对 ART 的反应。我们将使用我们开发的 SIVsab/PTM 模型实验室忠实地再现了 ART 和 CV 疾病中 SIV 发病机制的两个关键方面。我们将还使用了一种 NET 抑制剂，该抑制剂已通过小鼠动物模型的大量研究在体内得到验证。在初步研究表明，该药物能够通过以下方式抑制离体 NET 的产生：从感染 SIV 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 发病机制和疾病进展。为了实现这一目标，我们将在对未经治疗的 SIV 感染 PTM 进行慢性感染，并评估其对 SIV 感染自然史的影响，包括心血管合并症。这些实验旨在模拟那些没有接受治疗的感染者 ART或者ART上并没有实现完全的病毒抑制。其次，我们将检验 NETosis 的假设参与推动对 ART 的反应和 CV 合并症的发展。为了这个目标，我们将对经 ART 治疗的 SIV 感染 PTM 施用 NET 抑制剂并评估这种干预的后果 CD4+ T 细胞恢复、炎症、凝血和心血管疾病发展。这些实验是专为接受 ART 的 PWH 建模。这个高度创新的项目将增进我们对艾滋病毒的了解 HIV相关合并症的发病机制和机制，特别是心血管疾病，它是人类死亡的一个主要原因 PWH，因此可能对 PWH 的临床管理和生存产生关键影响。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neutrophil and Eosinophil Extracellular Traps in Hodgkin Lymphoma.

霍奇金淋巴瘤中的中性粒细胞和嗜酸性粒细胞胞外陷阱。

DOI：
发表时间：
2021-09
期刊：
影响因子：
6.6
作者：
Francischetti, Ivo M B;Alejo, Julie C;Sivanandham, Ranjit;Davies;Fetsch, Patricia;Pandrea, Ivona;Jaffe, Elaine S;Pittaluga, Stefania
通讯作者：
Pittaluga, Stefania