Platelet-mediated neuroinflammatory response to HIV

描述(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：每三个艾滋病毒-1生产性感染者中就有一个以上发展成某种形式的与艾滋病毒-1相关的神经认知障碍(HAND)，这种疾病对传统的抗病毒疗法仍然难以奏效。此外，在相当大比例的患者中，手部的临床症状被发现与其他全身炎症疾病的临床症状并存，其中一些与循环中激活的血小板数量较多有关。这可能表明，在这些感染者中，一种共同的潜在机制正在发挥作用。在这方面，HIV感染患者血浆中活化的血小板数量增加与免疫缺陷的严重程度有关，然而，尚不清楚血小板是否在Hand的发病机制中起关键作用。在这里，我们证明，全身应用生理相关水平的TAT会产生血浆中血小板激活的证据，随后是血脑屏障通透性增强和中枢神经系统炎症。当给最初耗尽血小板的动物注射TAT时，这些影响被取消，支持了血小板可能在手中发挥关键作用的观点。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脑微血管内皮细胞(BMVEC)的异常作用，从而改变血脑屏障(BBB)的完整性，加剧中枢神经系统的炎症。这项提案涉及三个根本性的关键问题。第一个问题是，艾滋病毒感染细胞释放的炎症介质是否也针对其他免疫效应细胞，如血小板(目标1)。第二，如果被激活，血小板反过来激活BMVEC，刺激与血脑屏障通透性有关的炎性血管变化(目标2)；最后，血小板引起的效应是否促进外周血单核细胞频繁通过正常的血脑屏障(目标3)。由此得出的明显推论是，对血小板活性的治疗操作是否提供了保护，使其免受艾滋病毒引起的神经损伤。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很大的翻译潜力。 与公共卫生相关：据推测，HIV-1参与了一种共同的机制，刺激身体不同部位的炎症性疾病。这一观点将通过调查血小板的异常激活是否导致观察到的艾滋病毒感染者的神经缺陷来检验。这些研究的结果有望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.