Platelet-mediated neuroinflammatory response to HIV

描述（由申请人提供）：经过近三十年的艾滋病流行，我们仍然面临这样一个事实的挑战，即超过三分之一的HIV-1生产感染患者会发展出某种形式的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性的。此外，在相当比例的患者中，HAND的临床症状与其他全身性炎症性疾病并存，其中一些与循环中活化血小板数量较高有关。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感染患者表现出血浆中活化血小板数量的增加，这与免疫缺陷的严重程度有关，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，我们证明了全身给予生理相关水平的Tat会产生血浆中血小板活化的证据，随后是血脑屏障的通透性增强和中枢神经系统的炎症。当将Tat用于血小板首先耗尽的动物时，这些影响被消除了，这支持了血小板可能在HAND中起关键作用的观点。基于这些发现，我们假设hiv -1感染细胞释放的效应分子激活外周血小板会引起对脑微血管内皮细胞（BMVEC）的异常影响，从而改变血脑屏障（BBB）的完整性并加剧中枢神经系统的炎症。这项建议涉及三个根本关键的问题。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）。其次，如果活化的血小板反过来激活BMVEC以刺激与血脑屏障通透性相关的炎性血管变化（Aim 2）；最后，血小板是否会促进外周血单核细胞频繁通过正常血脑屏障（目的3）。显而易见的推论是，对血小板活性的治疗性操作是否能保护机体免受HIV引起的神经损伤。因此，本文提出的实验对开发新的神经艾滋病治疗策略具有很大的转化潜力。

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.