Neuroimmune axis in HAND and HIV persistence in the brain
HAND 中的神经免疫轴和大脑中的 HIV 持续存在
基本信息
- 批准号:10088477
- 负责人:
- 金额:$ 55.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-20 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AccreditationAddressAgeAnimal ModelAnimalsAntiviral ResponseAstrocytesAutomobile DrivingAutopsyBloodBrainBrain InjuriesCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCellsChronicClinicalClinical ResearchCollaborationsDataEnvironmentExhibitsFrequenciesGenesGenetic TranscriptionHIVHIV InfectionsHIV-associated neurocognitive disorderHawaiiHumanImmuneIn VitroIndividualInfectionInflammationInflammatory ResponseInjuryInvadedLigandsMediatingMediator of activation proteinMilitary PersonnelModelingMusNervous System TraumaNeurocognitiveNeurocognitive DeficitNeuroimmuneNeurologic DeficitNeuronal InjuryNeuropathogenesisOutcomeParticipantPathogenicityPathway interactionsPatientsPerformancePeripheralPeripheral Blood Mononuclear CellPloidiesPopulationPublishingResearchResearch PersonnelRoleSIVSamplingSignal TransductionSiteSourceSoutheastern AsiaSurfaceSurveysT cell responseT-LymphocyteT-Lymphocyte SubsetsTestingTherapeutic InterventionUniversitiesViralVirusantimicrobialantiretroviral therapybasebeta catenincomorbiditycosthumanized mousein vivoinsightmigrationmotor impairmentnervous system disorderneuroAIDSneuroinflammationnovelnovel therapeutic interventionprogramsreconstitutionresponse
项目摘要
Abstract: HIV causes a spectrum of neurologic deficits known as HIV-Associated Neurologic
Disorders (HAND). HAND is a prominent co-morbid condition of HIV even in the era of
Combined Anti-Retroviral Therapy and is expected to increase as the HIV+ population ages.
Fundamental understanding of how HIV invades the brain and mechanisms that drive HAND
are poorly understood. In this application we will focus on the role of CD4+ T cells and
CD4dimCD8bright T cells in HIV neuroinvasion, persistence, and HAND. CD4dimCD8bright T cells
are a unique subset of CD8+ T cells that co-express CD4 on their surface. They exhibit potent
anti-viral responses in the periphery. Recently, we showed that migration of CD8+ T cells into
the CNS in context of HIV gives rise to CD4dimCD8bright T cells, in a Wnt/-catenin signaling -
dependent manner. Within the brain, CD4dimCD8bright T cells exhibit highly potent anti-HIV
responses. The consequence of this response is controlling HIV on one hand but perhaps at the
cost of inducing inflammation and injury in the brain. Based on our published and preliminary
data, we hypothesize that because peripheral CD4dimCD8bright T cells are susceptible to HIV
infection, they will contribute to HIV neuroinvasion (Aim 1), yet because they robustly express
-catenin and its pro-survival target gene, Bcl-XL, infected CD4dimCD8bright T cells will persist in
the CNS as a reservoir for HIV (Aim 2). Further, because CD4dimCD8bright mount potent anti-HIV
responses and are hyper-activated, their frequency will correlate with lower HIV content in CNS
but higher level of neuroinflamamtion and worse neurocognitive performance (Aim 3). We will
use a combination of in vitro, small animal studies, and patient samples from the Southeast Asia
Research Collaboration with the University of Hawaii (SEARCH) and the US Military HIV
Research Program (USMHRP) to address this central hypothesis. Collectively our studies will
establish a new understanding of HIV neuroinvasion, HIV neuro-persistence, and role of T cells
in the neuro-immune axis mediating neuropathogenesis/HAND. This understanding can provide
new approaches for therapeutic intervention to ameliorate and/or reduce HAND and will provide
valuable insights into HIV persistence in the CNS.
摘要:艾滋病毒引起一系列神经系统缺陷,称为艾滋病毒相关神经系统缺陷。
疾病(手)。即使在当今时代,手部疾病也是艾滋病毒的一种突出共病。
联合抗逆转录病毒疗法预计会随着 HIV+ 人口老龄化而增加。
对 HIV 如何侵入大脑以及驱动 HAND 的机制有基本了解
人们了解甚少。在此应用中,我们将重点关注 CD4+ T 细胞的作用和
CD4dimCD8bright T 细胞在 HIV 神经侵袭、持续性和 HAND 中的作用。 CD4dimCD8bright T 细胞
是 CD8+ T 细胞的一个独特子集,在其表面共表达 CD4。他们表现出强大的
外周的抗病毒反应。最近,我们发现 CD8+ T 细胞迁移到
HIV 背景下的中枢神经系统在 Wnt/-连环蛋白信号传导中产生 CD4dimCD8bright T 细胞 -
依赖方式。在大脑内,CD4dimCD8bright T 细胞表现出高效的抗 HIV 能力
回应。这种反应的结果是一方面控制了艾滋病毒,但也许另一方面
诱发大脑炎症和损伤的成本。根据我们已发布的和初步的
根据数据,我们假设由于外周 CD4dimCD8bright T 细胞容易感染 HIV
感染后,它们会导致 HIV 神经侵袭(目标 1),但因为它们强烈表达
-连环蛋白及其促生存靶基因 Bcl-XL,感染的 CD4dimCD8bright T 细胞将持续存在
中枢神经系统作为 HIV 的储存库(目标 2)。此外,由于 CD4dimCD8bright 具有有效的抗 HIV 作用
反应并且过度激活,其频率将与中枢神经系统中较低的 HIV 含量相关
但神经炎症水平更高,神经认知能力更差(目标 3)。我们将
结合体外、小动物研究和来自东南亚的患者样本
与夏威夷大学 (SEARCH) 和美国军方艾滋病毒研究合作
研究计划(USMHRP)旨在解决这一中心假设。总的来说,我们的研究将
对 HIV 神经侵袭、HIV 神经持久性和 T 细胞的作用建立新的认识
在介导神经发病机制/HAND 的神经免疫轴中。这种理解可以提供
改善和/或减少 HAND 的治疗干预新方法将提供
关于艾滋病毒在中枢神经系统中持续存在的宝贵见解。
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
HIV infection of non-classical cells in the brain.
- DOI:10.1186/s12977-023-00616-9
- 发表时间:2023-01-13
- 期刊:
- 影响因子:3.3
- 作者:
- 通讯作者:
CD32 is enriched on CD4dimCD8bright T cells.
- DOI:10.1371/journal.pone.0239157
- 发表时间:2020
- 期刊:
- 影响因子:3.7
- 作者:Virdi AK;Wallace J;Barbian H;Richards MH;Ritz EM;Sha B;Al-Harthi L
- 通讯作者:Al-Harthi L
Wnt/β-Catenin Protects Lymphocytes from HIV-Mediated Apoptosis via Induction of Bcl-xL.
- DOI:10.3390/v14071469
- 发表时间:2022-07-02
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
CD4 dim CD8 bright T cells are inversely associated with neuro-inflammatory markers among people with HIV.
- DOI:10.1097/qad.0000000000003743
- 发表时间:2024-01-01
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Lena Al-Harthi其他文献
Lena Al-Harthi的其他文献
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{{ truncateString('Lena Al-Harthi', 18)}}的其他基金
Human/Animal Brain Chimera in drugs of abuse and HIV
滥用药物和艾滋病毒中的人/动物脑嵌合体
- 批准号:
10543385 - 财政年份:2022
- 资助金额:
$ 55.13万 - 项目类别:
Human/Animal Brain Chimera in drugs of abuse and HIV
滥用药物和艾滋病毒中的人/动物脑嵌合体
- 批准号:
10683363 - 财政年份:2022
- 资助金额:
$ 55.13万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10063582 - 财政年份:2019
- 资助金额:
$ 55.13万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10524054 - 财政年份:2019
- 资助金额:
$ 55.13万 - 项目类别:
Dynamic interaction between HIV in the CNS and peripheral organs
HIV在中枢神经系统和周围器官中的动态相互作用
- 批准号:
10305639 - 财政年份:2019
- 资助金额:
$ 55.13万 - 项目类别:
Neuroimmune axis in HAND and HIV persistence in the brain
HAND 中的神经免疫轴和大脑中的 HIV 持续存在
- 批准号:
9474682 - 财政年份:2017
- 资助金额:
$ 55.13万 - 项目类别:
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