(PQ4) Role of HIV-induced PLK1 Activation in Regulation of gamma-Herpesvirus Reservoirs in Lymphocytes
(PQ4) HIV 诱导的 PLK1 激活在调节淋巴细胞中 γ-疱疹病毒储库中的作用
基本信息
- 批准号:10615879
- 负责人:
- 金额:$ 38.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-11 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AIDS-Related LymphomaAcquired Immunodeficiency SyndromeActivated B-LymphocyteActivated LymphocyteAddressAffectAntiviral AgentsApoptosisAttenuatedB-Cell NonHodgkins LymphomaB-LymphocytesBurkitt LymphomaCD4 Positive T LymphocytesCancer EtiologyCell Cycle ProgressionCell Cycle RegulationCell DeathCell ProliferationCell SurvivalCellsCellular TropismCessation of lifeChemicalsChromatinClinical TrialsDNA DamageDevelopmentDissectionDouble Stranded DNA VirusDrug CombinationsEpstein-Barr Virus latencyEtiologyHIVHIV InfectionsHIV SeropositivityHIV-1HerpesviridaeHerpesviridae InfectionsHumanHuman Herpesvirus 4Human Herpesvirus 8Immune signalingImmunocompromised HostImmunologic Deficiency SyndromesIndividualInfectionInfectious AgentInhibition of Cell ProliferationInvestigationKaposi SarcomaKnowledgeLifeLinkLymphocyteLymphoid CellLymphomaLymphoproliferative DisordersM cellMaintenanceMalignant NeoplasmsMediatingMemory B-LymphocyteMolecularMolecular TargetNasopharynx CarcinomaNon-Hodgkin&aposs LymphomaNuclearOncogenicOncolyticOrgan TransplantationOxidative StressPLK1 genePatientsPersonsPhosphotransferasesPlayPost-Translational Protein ProcessingPredispositionPrimary InfectionProcessProductionProtein-Serine-Threonine KinasesProteinsProto-OncogenesRegimenRegulationReportingResearchRestRiskRisk FactorsRoleSerineShockSignal TransductionSoft Tissue NeoplasmsSpecific qualifier valueStomach CarcinomaStressSumoylation PathwayT-LymphocyteTP53 geneTherapeuticViralViral ProteinsViral reservoirVirusVirus ActivationVirus DiseasesVirus Latencybiological adaptation to stresscancer therapycarcinogenesischronic infectionco-infectioneffective therapyfeasibility testinggammaherpesvirusinfected B cellinhibitorkinase inhibitorknock-downlarge cell Diffuse non-Hodgkin&aposs lymphomalatent infectionlytic replicationnef Proteinneoplastic cellnovelnovel therapeutic interventionoverexpressionpathogenpolo-like kinase kinase 1preventprimary effusion lymphomaresponsetargeted cancer therapytumorigenesisvirus related cancer
项目摘要
PROJECT SUMMARY
Gammaherpesvirus infections are associated with a number of malignancies that include B-cell
lymphoproliferative diseases, gastric carcinoma, nasopharyngeal carcinoma. Immunodeficient individuals such
as HIV patients are more susceptible to γ -herpesviruses-associated cancers. It generally takes several months
to years for cancer to arise after primary infection with the virus. This observation highlights the multistep
process of carcinogenesis that could only be achieved by viral persistent infection. EBV and KSHV are γ -
herpesviruses that establish latent infection in lymphoid cell, which is maintained for the rest of the host’s life.
Intermittent reactivation of these viral reservoirs will lead to more viruses production and spreading. Although
there are antiviral drugs that specifically target lytic replication of γ -herpesviruses, they do not eliminate those
latent viruses that could serve as a risk factor for viral-associated cancers.
Our group recently showed that HIV infection leads to activation of Polo-like kinase 1 (PLK1), a proto-
oncogene, in B and T-cell lymphocytes. PLK1 is a serine/threonine kinase that controls G2-M cell cycle
progression and is frequently overexpressed in wide range of cancers. Its inhibitors have been developed as
promising cancer therapy. We further discovered that PLK1 is involved in both regulation of EBV/KSHV latency
and survival of their cellular reservoirs in the host. Protein knockdown as well as chemical inhibition of PLK1
was able to reactivate latent EBV/KSHV and promote cell death of γ -herpesvirus-reactivated B lymphocytes.
These results expose a new viral mechanism that can describe how co-infection of γ -herpesviruses renders
HIV patients an increased risk to cancers, despite the fact that HIV itself is not oncogenic. Our investigations
into this topic will be accomplished by three separate aims that include: (1) Investigation of molecular
mechanism of PLK1 activation by HIV1 in EBV/KSHV-infected lymphocytes. (2) Investigation of how PLK1
regulates EBV/KSHV latency and maintenance of their cellular reservoirs. (3) Inhibition of PLK1 as novel
means to eradicate EBV/KSHV persistent infection by eliminating their cellular reservoirs.
Collectively, our proposed studies will contribute to the understanding of latency in HIV and
gammaherpesviruses infections that underlie various viral-associated cancers. This project will also help to
identify new molecular target for curing HIV and EBV/KSHV infections and their-related malignancies.
项目概要
伽马疱疹病毒感染与许多恶性肿瘤相关,其中包括 B 细胞恶性肿瘤
淋巴组织增生性疾病、胃癌、鼻咽癌等免疫缺陷个体。
由于艾滋病毒患者更容易患γ-疱疹病毒相关癌症,因此通常需要几个月的时间。
初次感染病毒后癌症的发生需要数年时间,这一观察结果强调了多步骤的过程。
只有通过病毒持续感染才能实现的致癌过程是γ-。
疱疹病毒在淋巴细胞中建立潜伏感染,并在宿主的余生中维持这种感染。
这些病毒库的间歇性重新激活将导致更多病毒的产生和传播。
有一些抗病毒药物专门针对 γ 疱疹病毒的裂解性复制,但它们并不能消除这些病毒
潜伏病毒可能成为病毒相关癌症的危险因素。
我们的小组最近表明,HIV 感染会导致 Polo 样激酶 1 (PLK1) 的激活,PLK1 是一种原
B 细胞和 T 细胞淋巴细胞中的癌基因 PLK1 是一种控制 G2-M 细胞周期的丝氨酸/苏氨酸激酶。
其抑制剂已被开发为多种癌症。
我们进一步发现 PLK1 参与 EBV/KSHV 潜伏期的调节。
以及它们的细胞储存库在宿主中的存活以及蛋白质敲除以及 PLK1 的化学抑制。
能够重新激活潜伏的 EBV/KSHV 并促进γ-疱疹病毒重新激活的 B 淋巴细胞的细胞死亡。
这些结果揭示了一种新的病毒机制,可以描述γ-疱疹病毒的共同感染如何导致
尽管艾滋病毒本身并不致癌,但艾滋病毒患者患癌症的风险增加。
该主题将通过三个不同的目标来完成,包括:(1)分子生物学的研究
HIV1在EBV/KSHV感染的淋巴细胞中激活PLK1的机制(2)PLK1如何激活的研究。
调节 EBV/KSHV 潜伏期及其细胞储存库的维持 (3) 抑制 PLK1 作为新型药物。
指通过消除细胞储存库来根除 EBV/KSHV 持续感染。
总的来说,我们提出的研究将有助于了解艾滋病毒的潜伏期和
该项目也将有助于研究导致各种病毒相关癌症的伽玛疱疹病毒感染。
确定治疗 HIV 和 EBV/KSHV 感染及其相关恶性肿瘤的新分子靶标。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.
- DOI:10.1371/journal.ppat.1010503
- 发表时间:2022-04
- 期刊:
- 影响因子:6.7
- 作者:
- 通讯作者:
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Netty G Santoso其他文献
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{{ truncateString('Netty G Santoso', 18)}}的其他基金
(PQ4) Role of HIV-induced PLK1 Activation in Regulation of gamma-Herpesvirus Reservoirs in Lymphocytes
(PQ4) HIV 诱导的 PLK1 激活在调节淋巴细胞中 γ-疱疹病毒储库中的作用
- 批准号:
10228415 - 财政年份:2021
- 资助金额:
$ 38.81万 - 项目类别:
(PQ4) Role of HIV-induced PLK1 Activation in Regulation of gamma-Herpesvirus Reservoirs in Lymphocytes
(PQ4) HIV 诱导的 PLK1 激活在调节淋巴细胞中 γ-疱疹病毒储库中的作用
- 批准号:
10403994 - 财政年份:2021
- 资助金额:
$ 38.81万 - 项目类别:
Inhibition of TIP60 by Latent Gammaherpesviruses in B-cell Lymphomas
B 细胞淋巴瘤中潜伏的伽玛疱疹病毒对 TIP60 的抑制
- 批准号:
10012305 - 财政年份:2020
- 资助金额:
$ 38.81万 - 项目类别:
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