Viral Protein R (Vpr) in HIV-associated Brain Neuroinflammation and Neurotoxicity

病毒蛋白 R (Vpr) 在 HIV 相关脑神经炎症和神经毒性中的作用

基本信息

批准号：
10664939
负责人：
J. Marc Simard
金额：
--
依托单位：
BALTIMORE VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664939
关键词：
Address Affect Aging Antiviral Therapy Astrocytes Autopsy Binding Biochemical Brain Brain Injuries Cations Cell Line Cells Central Nervous System Central Nervous System Infections Chronic Data Delirium Dementia Extracellular Space FDA approved Genetic Genetic Transcription Glyburide Goals HIV HIV-1 HIV-associated neurocognitive disorder HIV/AIDS Healthcare Human Immune Impairment Individual Induction of Apoptosis Infection Inflammatory Inflammatory Response International Knockout Mice Link Longevity Macrophage Mediating Mental Depression Mental Health Methods Microglia Molecular Mus NF-kappa B Neurocognitive Neurocognitive Deficit Neuroglia Neurologic Neurons Neuropathogenesis Neurotoxins Patients Persons Pharmaceutical Preparations Pilot Projects Play Proteins Reporting Research Priority Residual state Role Severities Source Suicide Surgeon TLR4 gene TNF gene Testing Therapeutic Transgenic Mice Transgenic Organisms United States Department of Veterans Affairs Veterans Viral Viral Load result Viral Proteins Virion Virus Virus Replication antiretroviral therapy blood-brain barrier crossing brain tissue chemokine cytokine experience glial activation improved inflammatory marker insight neurocognitive disorder neuroinflammation neuron apoptosis neuropathology neurotoxic neurotoxicity novel particle pharmacologic promoter reactivation from latency suicidal risk suicide mortality virus host interaction vpr Gene Products

项目摘要

This proposed project has direct relevance to Veteran healthcare because it addresses current VA’s research priority on how HIV-1 infection causes brain damages that affect Veteran’s mental health including HIV- associated neurocognitive disorders (HAND) and suicide. There are about 37 million people currently living with HIV/AIDS worldwide. Successful treatment with combinational antiretroviral therapies (cART) can eliminate active replicating viruses and prolong patients’ lives to nearly normal lifespans. However, the new challenge faced by more than half of those HIV-infected and aging patients is the chronic CNS neuroinflammation, which leads to various HAND. While severe and progressive HAND has decreased significantly due to cART, chronic HANDS often persists, resulting in high rates of delirium, dementia and depression that could lead to suicide. Indeed, “the risk of suicide mortality in HIV-infected persons is 3-5 times higher than in HIV-uninfected counterparts”. Nevertheless, the mechanism of neuropathogenesis underlying HAND is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. Interestingly, the severity of some HAND does not always directly correlate with the levels of HIV, but rather with glial activation, suggesting other HIV-associated factors, not the whole virus per se, contribute to those HAND. HIV-1 viral protein R (Vpr) might be one of those viral factors, because Vpr induces neuroinflammation and causes neuronal apoptosis. Moreover, in the absence of active viral replication under cART, Vpr can be found in CNS-associated cells because 1) it can be released directly from viral particles; 2) it crosses the blood-brain barrier that can be taken up by glia and neurons; and 3) it triggers viral transcription of latently-infected cells by binding to LTR promoter. Despite these strong evidences indicating a prominent role of Vpr in HAND, how exactly Vpr contributes to HAND remains elusive. The objective of this proposal is to study the specific role(s) of Vpr in activation of host neuroinflammation, neurotoxicity and viral reactivation, as well as its contribution to HAND. Through our pilot studies, we discovered correlations between HIV expression and activation of proinflammatory markers (TLR4, TNFα, NF-κB and the Sur1-Trpm4 channel) in astrocytes of HIV-infected postmortem human and transgenic mouse brain tissues. Furthermore, Vpr alone activate the same set of markers in glial cells. The connection between Vpr and the Sur1-Trpm4 channel could potentially be significant for understanding HAND because this channel is a key neuro-regulator involved in various neurocognitive brain conditions. Indeed, inhibition of the channel by a repurposed and FDA-approved drug glibenclamide reduces Vpr-induced apoptosis and improves other neuroinflammatory brain conditions. Thus, our pilot studies may have revealed a novel mechanism of HAND involving Vpr-induced activation of the Sur1-Trpm4 channel. Therefore, we hypothesize that Vpr contributes to HAND by TLR4/MyD88- and/or TNFα-mediated NF-κB activation, which in turn upregulate the Sur1-Trpm4 channel leading to neuroinflammation and neurotoxicity. Alternatively, Vpr- induced HAND is contributed collectively by NF-κB and Sur1-Trpm4-mediated neuropathologic effects. We further hypothesize that target-specific inhibition of key regulators such as the Sur1-Trpm4 channel mitigates Vpr-induced HAND. We will test these hypotheses with three specific aims (SA). SA1: delineate molecular mechanism of Vpr-induced neuroinflammation, neurotoxicity and viral reactivation in primary astrocytes; SA2: test the functional link of Vpr with the Sur1-Trpm4 channel, its interaction with NF-kB and its contribution to Vpr- induced HAND; and SA3: evaluate the effects of genetic and pharmacologic inhibitions of the Sur1-Trpm4 channel on Vpr-induced HAND by using knock-out mice and by target-specific therapeutic drugs such as glibenclamide. Successful completion of this project will provide novel insights into 1) the molecular mechanism and contribution of HIV-1 Vpr to HAND, 2) the functional link between Vpr and the Sur1-Trpm4 channel and its contribution to HAND, and 3) the feasibility of treating Vpr-related HAND with the therapeutic drug glibenclamide.

这个拟议的项目与资深医疗保健有直接相关性，因为它解决了当前VA的研究优先考虑HIV-1感染如何造成影响退伍军人心理健康的大脑损害，包括HIV- 相关的神经认知障碍（手）和自杀。目前约有3700万人与艾滋病毒/艾滋病在全球。联合抗逆转录病毒疗法（CART）成功治疗可以消除主动复制病毒并将患者的寿命延长至正常的寿命。但是，新的挑战慢性中枢神经系统神经炎症是由超过一半的艾滋病毒感染和衰老患者面临的导致各种手。虽然由于购物车而严重而渐进的手显着减少了双手经常持续，导致ir妄，痴呆和抑郁症的高率可能导致自杀。实际上，“艾滋病毒感染者自杀死亡率的风险比未感染的艾滋病毒高3-5倍同类”。然而，尚不清楚神经病生成的机制。手通常以HIV介导的神经神经炎症和神经毒性为特征。有趣的是，某些手的严重程度并不总是与艾滋病毒的水平直接相关，而是与神经胶质激活相关，提示其他与HIV相关的因素，而不是整个病毒本身，对这些因素有贡献。 HIV-1病毒蛋白 R（VPR）可能是这些病毒因素之一，因为VPR诱导神经炎症并引起神经元凋亡。此外，在CART下没有主动病毒复制的情况下，可以在CNS相关的细胞是因为1）可以直接从病毒颗粒中释放出来； 2）它可以越过血脑屏障被神经胶质和神经元吸收； 3）它通过与LTR结合而触发潜在感染细胞的病毒转录发起人。尽管这些有力的证据表明VPR在手中的重要作用，但如何确切地有助于手仍然难以捉摸。该提案的目的是研究VPR的特定作用宿主神经炎症，神经毒性和病毒重新激活的激活及其对手的贡献。通过我们的试点研究，我们发现了HIV表达与激活之间的相关性 HIV感染的星形胶质细胞中的促炎标记（TLR4，TLR4，TNFα，NF-κB和SUR1-TRPM4通道）验尸后人类和转基因小鼠脑组织。此外，仅VPR激活相同的集合神经胶质细胞中的标记。 VPR和SUR1-TRPM4通道之间的连接可能很重要理解手，因为此通道是参与各种神经认知大脑的关键神经调节剂状况。实际上，通过重新使用和FDA批准的药物抑制通道的抑制作用减少了 VPR诱导的细胞凋亡并改善其他神经炎症性脑疾病。那，我们的试点研究可能揭示了一种新型的手部机制，涉及VPR诱导的SUR1-TRPM4通道激活。所以，我们假设VPR有助于TLR4/MYD88-和/或TNFα介导的NF-κB激活，这有助于其手。反过来又上调了SUR1-TRPM4通道，导致神经炎症和神经毒性。或者，vpr- 诱导的手由NF-κB和SUR1-TRPM4介导的神经病理学效应共同贡献。我们进一步假设目标特异性抑制关键调节剂（例如SUR1-TRPM4通道）减轻 VPR引起的手。我们将以三个特定目标（SA）来检验这些假设。 SA1：描绘分子初级星形胶质细胞中VPR诱导的神经炎症，神经毒性和病毒重新激活的机制； SA2：测试VPR与SUR1-TRPM4通道的功能链接，与NF-KB的相互作用及其对VPR-的贡献诱发的手；和SA3：评估SUR1-TRPM4的遗传和药物抑制的影响通过使用敲除小鼠和靶标特异性治疗药物（例如） Glibenclamide。该项目的成功完成将为1）分子机制提供新的见解 HIV-1 VPR的贡献，2）VPR与SUR1-TRPM4通道之间的功能链接及对手的贡献，以及3）用治疗性药物Glibenclamide治疗与VPR相关的手的可行性。