Impact of NETosis on SIV Pathogenesis and Response to Treatment

抗逆转录病毒疗法(ART)极大地改变了慢性HIV感染的面貌 降低艾滋病毒感染者的死亡率(PWH)。然而，许多PWH表现为肠道功能障碍，残留 免疫激活和炎症，不完全的免疫恢复和高凝状态，所有这些 导致不良的预后和非艾滋病共病的发展，如心血管疾病(CVD)。 感染PWH和SIV的猕猴心血管疾病发生的途径还不完全 已澄清。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)的过度激活和过度产生。通过研究 Net在SIV感染中的动态和功能，我们表明它们可能在疾病进展中起作用 和合并症：(A)在未经治疗的SIV感染期间，促炎性蚊虫增多，并且只有 经ART部分减少，(B)Net可能是免疫细胞不分青红皂白耗尽的决定因素， 不是病毒靶标，以及在ART上观察到的PWH中CD4+T细胞的不完全恢复，以及(C)网织红细胞增多症 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蚊虫感染在HIV疾病进展中的作用。 以及通过体内直接干预对ART的反应。我们将使用在我们的 实验室忠实地再现了SIV在ART和心血管疾病上的发病机制的关键方面。我们会 也使用一种已在体内通过大量小鼠动物模型研究证实的网络抑制剂。在……里面 初步研究表明，该药物可通过以下途径抑制NETs的体外产生 从我们的SIV感染的PTM中分离出中性粒细胞。我们将首先测试NETsis涉及的假设 推动SIV的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感染的PTM进行慢性感染，并评估其对SIV感染自然病史的影响； 包括心血管并发症。这些实验被设计用来模拟那些没有收到 ART还是不能完全实现对ART病毒的抑制。其次，我们将检验这样一种假设，即蚊虫肺炎 参与推动对ART的反应和心血管合并症的发展。为了实现这个目标，我们将 对ART治疗的SIV感染的PTM给予Net抑制剂，并评估这种干预的后果 关于CD4+T细胞的恢复、炎症、凝血和心血管疾病的发展。这些实验是 为PWH设计的模特，他们接受艺术。这一极具创新性的项目将提高我们对艾滋病毒的了解 艾滋病毒相关合并症的发病和机制，特别是心血管病，这是#年的主要死亡原因 因此，可能对威斯康星医院的临床管理和生存有重要影响。

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.