A radiation-induced cellular stress activates HIV and induces killing of infected cells
辐射引起的细胞应激会激活艾滋病毒并诱导杀死受感染的细胞
基本信息
- 批准号:9212863
- 负责人:
- 金额:$ 19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-08-15 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AgonistAnti-Retroviral AgentsApoptosisAutophagocytosisBindingCASP1 geneCD4 Positive T LymphocytesCell Culture TechniquesCell CycleCell DeathCell LineCell SurvivalCellsCellular StressCessation of lifeCyclinsDNA DamageDNA Polymerase IIDataDoseEpigenetic ProcessGenetic TranscriptionGenomeGoalsHDAC1 geneHIVHIV-1Highly Active Antiretroviral TherapyHumanImmune responseImmune systemIndividualInduction of ApoptosisInterleukin-7LifeMethodsMusNuclearOrganOutcomePatientsPharmaceutical PreparationsPhosphorylationPlasmaPopulationPositive Transcriptional Elongation Factor BProductionProteasome InhibitorPublishingRNARNA Polymerase IIRadiationRestReverse Transcriptase Polymerase Chain ReactionRoentgen RaysS PhaseSchemeShockSignal TransductionSpecificityStressT-LymphocyteTP53 geneTestingTherapeuticTissuesTranscriptional ActivationTransferaseViralViral ProteinsViral reservoirVirusVirus ReplicationWestern BlottingWorkbryostatincalpain inhibitorcancer therapychromatin immunoprecipitationcytotoxichumanized mousein vivoinhibitor/antagonistirradiationkillingsmacrophagepromoterrepairedresponsetranscription factorviral RNA
项目摘要
HIV-1 can be preserved in the long-lived resting CD4+ T cells which form a viral reservoir in infected
individuals. This reservoir may persist for many years even though the patients are usually treated
with highly active antiretroviral therapy (HAART), and viral population can be recovered once
HAART is stopped. Thus, the selective activation of the latently HIV-infected cells resulting in the
replication of proviral genome is critical to make infected cells recognized by immune system. Our
long term goal is to find the method of reactivation of HIV from latency and killing of infected cells
that does not kill or destroy non-infected quiescent cells and subsequently target and eradicate the
persistent HIV-1 reservoirs. We have preliminary data showing that a well-characterized stress
signal, such as irradiation (IR), activated inappropriate entry of the HIV infected T cells to S phase of
the cell cycle and increased viral transcription and eventual apoptosis of infected cells. Importantly,
the parental uninfected cells did not demonstrate this response to the same irradiation dose. Our
recently published data elucidated this phenomenon and indicated (1) increase of HIV-1
transcription via epigenetic mechanisms after the IR-induced DNA damage, as evidenced by the
presence of RNA polymerase II and reduction of HDAC1 and methyl transferase SUV39H1 on the
HIV-1 promoter; (2) elevated level of intracellular HIV-1 RNA and increased expression of viral
proteins in the IR-treated HIV-1 infected quiescent CD4+ T cells; (3) enhancement of transcription
activation in latently HIV-1infected macrophages treated with PKC agonist bryostatin 1 after IR; (4)
higher death of irradiated HIV-1 chronically-infected cells via increased phosphorylation of Ser46 in
p53 that is responsible for apoptosis induction. Finally, (5) exposure of HIV-1 infected humanized
mice with undetectable viral RNA level to IR resulted in a significant increase of HIV-1 RNA in
plasma and certain tissue viral reservoirs. We hypothesize, that the cellular stress induced by low IR
doses reactivates HIV-1 transcription from latently infected cells resulting in nuclear accumulation of
Tat, activation of HIV-1 genome expression and enhanced apoptosis of infected, but not uninfected,
cells. Our two aims include; A) To identify the mechanism of HIV-1 reactivation in response to
therapeutic X-ray doses in latently infected T cells and to assess IR effect on the Tat activated HIV-1
transcription; and B) To decipher mechanism of enhanced apoptosis of HIV-1 infected cells in
response to IR doses. The expected outcomes of these proposed studies include elucidation of the
mechanisms that determine HIV-1 reactivation and apoptosis in latently infected cells and tissues in
response to the X ray IR. We also expect to determine optimal IR dose that does not destroy
uninfected cells, but induces HIV-1 reactivation and apoptosis of latently infected cells.
HIV-1可以保存在长寿命的静息CD 4 + T细胞中,这些T细胞在感染者中形成病毒库。
个体即使患者通常接受治疗,这种储库也可能持续多年
高效抗逆转录病毒治疗(HAART),病毒种群可一次性恢复
HAART停止了。因此,潜伏HIV感染细胞的选择性激活导致了HIV感染的发生。
前病毒基因组的复制是使感染细胞被免疫系统识别的关键。我们
长期目标是找到从潜伏期和杀死感染细胞中重新激活HIV的方法
不杀死或破坏未感染的静止细胞,随后靶向并根除
持续的HIV-1储存库。我们有初步的数据表明,一个很好的特点压力,
信号,如辐射(IR),激活HIV感染的T细胞不适当地进入S期,
细胞周期和增加的病毒转录和最终的受感染细胞的凋亡。重要的是,
未感染的亲本细胞对相同的辐射剂量没有表现出这种反应。我们
最近发表的数据阐明了这一现象,并表明(1)HIV-1的增加
转录通过表观遗传机制后,IR诱导的DNA损伤,证明了这一点,
RNA聚合酶II的存在以及HDAC 1和甲基转移酶SUV 39 H1在细胞表面的减少,
HIV-1启动子;(2)细胞内HIV-1 RNA水平升高和病毒表达增加
IR处理的HIV-1感染的静止期CD 4 + T细胞中的蛋白质;(3)转录增强
IR后PKC激动剂苔藓抑素1处理的潜伏性HIV-1感染的巨噬细胞中的活化;(4)
通过增加Ser 46的磷酸化,
p53是负责细胞凋亡诱导的。最后,(5)暴露HIV-1感染的人源化
病毒RNA水平检测不到的小鼠IR导致HIV-1 RNA的显著增加,
血浆和某些组织病毒库。我们推测,低IR诱导的细胞应激
剂量重新激活潜伏感染细胞的HIV-1转录,
达特,HIV-1基因组表达的激活和感染者的细胞凋亡的增强,但未感染者的细胞凋亡没有增强,
细胞我们的两个目标包括:A)确定HIV-1重新激活的机制,
潜伏感染T细胞的治疗X射线剂量,并评估IR对达特活化HIV-1的作用
B)为了解释HIV-1感染的细胞的凋亡增强的机制,
对IR剂量的反应。这些拟议研究的预期成果包括阐明
HIV-1在潜伏感染的细胞和组织中的再活化和凋亡的机制,
我们还希望确定不破坏X射线IR的最佳IR剂量,
未感染的细胞,但诱导HIV-1再活化和潜在感染细胞的凋亡。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)
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Fatah Kashanchi其他文献
Fatah Kashanchi的其他文献
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{{ truncateString('Fatah Kashanchi', 18)}}的其他基金
American Society for Intercellular Communication (ASIC)
美国细胞间通讯学会 (ASIC)
- 批准号:
10753704 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
Cell-derived extracellular vesicle mediated epigenetic silencing of HIV in the brain
细胞源性细胞外囊泡介导大脑中HIV的表观遗传沉默
- 批准号:
10748545 - 财政年份:2023
- 资助金额:
$ 19万 - 项目类别:
American Society for Intercellular Communication (ASIC)
美国细胞间通讯学会 (ASIC)
- 批准号:
10539845 - 财政年份:2022
- 资助金额:
$ 19万 - 项目类别:
Effect on CBD on Exosome release from CNS infected cells
CBD 对中枢神经系统感染细胞外泌体释放的影响
- 批准号:
9884894 - 财政年份:2020
- 资助金额:
$ 19万 - 项目类别:
Role of extracellular vesicles in methamphetamine and HIV induced neurotoxicity
细胞外囊泡在甲基苯丙胺和 HIV 诱导的神经毒性中的作用
- 批准号:
9929090 - 财政年份:2018
- 资助金额:
$ 19万 - 项目类别:
A radiation-induced cellular stress activates HIV and induces killing of infected cells
辐射引起的细胞应激会激活艾滋病毒并诱导杀死受感染的细胞
- 批准号:
9326140 - 财政年份:2016
- 资助金额:
$ 19万 - 项目类别:
HIV neuropathogenesis related to exosomes containing HIV non-coding RNAs
与含有 HIV 非编码 RNA 的外泌体相关的 HIV 神经发病机制
- 批准号:
9136536 - 财政年份:2016
- 资助金额:
$ 19万 - 项目类别:
HIV neuropathogenesis related to exosomes containing HIV non-coding RNAs
与含有 HIV 非编码 RNA 的外泌体相关的 HIV 神经发病机制
- 批准号:
9893927 - 财政年份:2016
- 资助金额:
$ 19万 - 项目类别:
Effect of novel cdk9 inhibitor on HIV transcription
新型cdk9抑制剂对HIV转录的影响
- 批准号:
8793029 - 财政年份:2014
- 资助金额:
$ 19万 - 项目类别:
Effect of novel cdk9 inhibitor on HIV transcription
新型cdk9抑制剂对HIV转录的影响
- 批准号:
8894397 - 财政年份:2014
- 资助金额:
$ 19万 - 项目类别:
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