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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.

这个拟议的项目与退伍军人医疗保健直接相关，因为它解决了当前退伍军人事务部的研究