Platelet-mediated neuroinflammatory response to HIV

血小板介导的 HIV 神经炎症反应

• 批准号: 8215723
• 负责人: SANJAY B. MAGGIRWAR
• 金额: $ 42.43万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215723
• 关键词: AIDS neuropathy; Accounting; Acquired Immunodeficiency Syndrome; Address; Adhesions; Animals; Antiviral Agents; Astrocytes; Biological Assay; Bleeding time procedure; Blood - brain barrier anatomy; Blood Circulation; Blood Platelets; Blood Substitutes; Blood Vessels; Brain; Cells; Clinical; Conditioned Culture Media; Development; Disease; Dose; Dyes; Effector Cell; Endothelial Cells; Epidemic; Evans blue stain; Exclusion; Exhibits; Exposure to; Gene Expression; Genetic; HIV; HIV Envelope Protein gp120; HIV-1; Hemostatic function; Human; Image; Immune; Immunologics; Impaired cognition; Individual; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Knockout Mice; Lead; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Modeling; Mus; Neurocognitive; Neurologic; Neurologic Deficit; Outcome Study; P-Selectin; Pathogenesis; Pathway interactions; Patients; Penetration; Peripheral; Permeability; Physiological; Plasma; Platelet Activating Factor; Platelet Activation; Play; Process; Refractory; Regulation; Role; Severities; Side; Symptoms; TNFSF5 gene; Tail; Testing; Therapeutic; Viral Proteins; Work; base; cell type; cytokine; follow-up; in vivo; inhibitor/antagonist; intravenous injection; migration; mixed lineage kinase 3; monocyte; novel therapeutics; peripheral blood; public health relevance; research study; response

DESCRIPTION (provided by applicant): After almost three decades of AIDS epidemic, we are still challenged with the fact that more than one out of three people with productive infection of HIV-1 develops some form of HIV-1 associated neurocognitive disorder (HAND), which remains refractory to the conventional antiviral therapeutics. In addition, the clinical symptoms of HAND are found to coexist with those of other systemic inflammatory diseases in a significant proportion of patients, some of which are associated with a higher number of activated platelets in the circulation. This may suggest that a common underlying mechanism is at work in these infected individuals. In this respect, HIV-infected patients exhibit increased numbers of activated platelets in the plasma in a manner that relates to the severity of the immunologic deficit, however, it is unknown whether platelets play a pivotal role in the pathogenesis of HAND. Here we demonstrate that the systemic administration of physiologically relevant levels of Tat produces evidence of platelet activation in the plasma, followed by enhanced permeability of the BBB and inflammation in the CNS. These effects were abolished when Tat was administered to animals that had first been depleted of platelets, supporting the notion that platelets might play a crucial role in HAND. Based on these findings, we hypothesize that the activation of peripheral platelets by effector molecules released by HIV-1-infected cells elicits abnormal effects on brain microvascular endothelial cells (BMVEC), thereby altering blood-brain barrier (BBB) integrity and exacerbating inflammation in the CNS. Three fundamentally critical questions are addressed in this proposal. The first is whether inflammatory mediators released by HIV-infected cells also target other immune effector cells, such as platelets (Aim 1). Second, if activated platelets in turn activate BMVEC to stimulate inflammatory vascular changes that are connected with BBB permeability (Aim 2); and last whether the effects caused by platelets facilitate frequent passage of peripheral blood monocytes through an otherwise normal BBB (Aim 3). The obvious corollary to this is whether therapeutic manipulation of platelet activity provides protection from neurologic damages induced by HIV. Thus, the experiments proposed herein have great translational potential for the development of new therapeutic strategies for neuroAIDS. PUBLIC HEALTH RELEVANCE: It is speculated that a common mechanism is engaged by HIV-1 to stimulate inflammatory disorders in various body compartments. This notion will be tested by investigating whether the abnormal activation of blood platelets accounts for the observed neurologic deficits in HIV-infected individuals. The outcome of these studies is expected to further our understanding of disease, which ultimately will lead to new therapeutic strategies.

描述（由申请人提供）：经过将近三十年的艾滋病流行病，我们仍然受到挑战：三分之一的HIV-1生产性感染HIV-1的人中有多个形式的HIV-1相关神经认知障碍（HARD），这些神经认知障碍（HARD）仍然对常规抗病毒治疗药物仍然具有难以证实。此外，发现手的临床症状与大部分患者的其他全身性炎症性疾病共存，其中一些患者与循环中激活的血小板数量较高有关。这可能表明，在这些受感染的个体中，一种共同的潜在机制正在起作用。在这方面，感染HIV的患者以与免疫缺陷的严重程度有关的方式表现出增加血小板的数量，但是，尚不清楚血小板在手的发病机理中是否起关键作用。在这里，我们证明了在生理相关水平的TAT水平的全身施用会产生血浆中血小板激活的证据，然后在中枢神经系统中BBB和炎症的渗透性增强。当将TAT施用到首次耗尽血小板的动物时，这些作用被废除了，这支持了血小板在手上起着至关重要的作用的观念。基于这些发现，我们假设由HIV-1感染细胞释放的效应分子激活外周血血小板会引起对脑微血管内皮细胞（BMVEC）的异常作用，从而改变了血脑屏障（BBB）的血脑屏障（BBB）完整性和cns中的炎症。本提案中解决了三个根本关键的问题。首先是由HIV感染细胞释放的炎症介质是否还针对其他免疫效应细胞，例如血小板（AIM 1）。其次，如果激活的血小板反过来激活BMVEC以刺激与BBB渗透性相关的炎症性血管变化（AIM 2）；最后，血小板引起的作用是否有助于频繁通过外周血单核细胞通过原本正常的BBB（AIM 3）。显而易见的推论是，对血小板活性的治疗操作是否可保护HIV诱导的神经系统损害。因此，本文提出的实验具有巨大的转化潜力，可以开发新的神经助剂治疗策略。 公共卫生相关性：据推测，HIV-1涉及一种共同的机制，以刺激各种身体室中的炎症性疾病。该概念将通过研究血小板的异常激活是否解释了观察到的HIV感染者的神经系统缺陷。这些研究的结果预计将进一步了解我们对疾病的理解，这最终将导致新的治疗策略。