Platelet-mediated neuroinflammatory response to HIV

描述（由申请人提供）：在艾滋病流行近30年后，我们仍然面临这样一个事实的挑战，即三分之一以上的HIV-1感染者发展出某种形式的HIV-1相关神经认知障碍（HAND），这对传统的抗病毒治疗仍然是难治的。此外，发现HAND的临床症状在相当大比例的患者中与其他全身性炎性疾病的临床症状共存，其中一些与循环中较高数量的活化血小板相关。这可能表明，在这些受感染的个体中有一种共同的潜在机制在起作用。在这方面，HIV感染患者血浆中活化血小板数量增加，与免疫缺陷的严重程度相关，然而，血小板是否在HAND的发病机制中起关键作用尚不清楚。在这里，我们证明了全身施用生理相关水平的达特产生血浆中血小板活化的证据，随后是BBB的渗透性增强和CNS中的炎症。当达特给药于血小板首先耗尽的动物时，这些作用被消除，支持血小板可能在HAND中起关键作用的观点。基于这些发现，我们假设，激活外周血小板的效应分子释放的HIV-1感染的细胞elevened异常影响脑微血管内皮细胞（BMVEC），从而改变血脑屏障（BBB）的完整性，并加剧炎症在中枢神经系统。本提案涉及三个根本性的关键问题。首先是HIV感染细胞释放的炎症介质是否也靶向其他免疫效应细胞，如血小板（Aim 1）。第二，如果活化的血小板反过来活化BMVEC以刺激与BBB渗透性相关的炎性血管变化（目的2）;以及最后由血小板引起的效应是否促进外周血单核细胞频繁通过原本正常的BBB（目的3）。这一点的明显推论是，血小板活性的治疗性操作是否能防止HIV引起的神经损伤。因此，本文提出的实验对于开发神经艾滋病的新治疗策略具有巨大的转化潜力。 公共卫生相关性：据推测，一个共同的机制是从事由HIV-1刺激炎症疾病在各种身体隔室。这一观点将通过研究血小板的异常活化是否是HIV感染者神经功能缺损的原因来检验。这些研究的结果有望进一步加深我们对疾病的理解，最终将导致新的治疗策略。

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.