Mechanisms of Neuro-AIDS by HIV 1B and C Clades
HIV 1B 和 C 进化枝导致神经艾滋病的机制
基本信息
- 批准号:8245854
- 负责人:
- 金额:$ 33.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-05 至 2015-02-28
- 项目状态:已结题
- 来源:
- 关键词:AIDS Dementia ComplexAbbreviationsAcquired Immunodeficiency SyndromeAffectAfrica South of the SaharaAnti-Inflammatory AgentsAnti-inflammatoryAntiviral AgentsAsiaAstrocytesAttenuatedBrainCCL2 geneCellsClinicalCognitiveComplementCountryDementiaDendritic CellsDeveloping CountriesDevelopmentDisease ProgressionEnzymesEuropeExperimental ModelsFamilyFutureGene ExpressionGenetic VariationHIVHIV InfectionsHIV diagnosisHIV-1HumanImmune responseIn VitroIndiaInfectionInflammatoryInositolInstitutesIntegration Host FactorsInterleukin-6InvestigationKynurenineMAPK14 geneMacrophage Inflammatory Protein-1Macrophage Inflammatory ProteinsMediatingMedicalMicrogliaMilitary PersonnelMinorMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesModelingNeuraxisNeurologicNeuronsNeuropathogenesisNeurotoxinsNomadsOrganPathogenesisPatientsPeptidesPhosphotransferasesPopulationPreventiveProductionPropertyProtein KinaseProteinsQuinolinic AcidRANTESRecombinantsRegulationReportingRiskRoleSignal Transduction PathwaySmall Interfering RNAT-Cell ActivationTNF geneTherapeuticTimeUnited StatesVaccinesViralVirusVirus DiseasesWestern Worldchemokinecytokinedesignfrontal lobeindolamineinhibitor/antagonistmacrophagemembermethyl tryptophanmitogen-activated protein kinase p38monocytemotor disorderneurotoxicnovelnovel strategiespandemic diseasepreventpublic health relevancestress activated protein kinasestress-activated protein kinase 1therapeutic target
项目摘要
DESCRIPTION (provided by applicant): The predominant HIV-1 subtype found in US and Western World is clade B, which differs significantly from clade C that exists in sub-Saharan Africa and Asia. Estimates suggest that out of about 33.2 million people infected with HIV-1, about 60% of the infection is with clade C alone and HIV-1C infection is rapidly spreading to other parts of the world. AIDS is often accompanied by neuropathological abnormalities. Current understandings of HIV-1 neuropathogenesis emanate from B clade from U.S and Western countries and very little information is available on neuropathogenesis of C clade. We hypothesize that clade B and C exert differential effects on CNS cells leading to differential neuropathogenesis and the mechanisms may be mediated by dysregulation of mitogen activated protein (MAP) kinases signal transduction pathways. Accordingly we will study for the first time :(Aim #1a) the effects of in vitro infection with clade B and C virus on production and gene expression of pro-inflammatory cytokines (TNF1 & IL-6), chemokines (MCP-1 & RANTES), and neurotoxin (IDO) by primary monocytes and CNS cells (astrocytes, microglial cells) and examine (Aim #1b), whether the mechanism of differential dysregulation induced by clade specific virus infection is mediated by modulation of mitogen activated protein (MAP) kinases signal transduction pathways. Further these in vitro infection studies will be compared, correlated and complemented with ex vivo studies (Aim #2) using monocytes from HIV-1B infected subjects being studied in Miami and HIV-1C infected subjects being studied at the collaborating institute in India. The results emanating from these studies may a) unravel the differential effect of clade specific infection on neuropathogenesis, b) help to develop therapeutically useful agents which could attenuate or prevent the neuropathogenesis associated with clade specific HIV-1 infection and c) design novel strategies to develop preventive and therapeutic global vaccines that can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States where non B subtypes have been recently reported in migrant populations and among our military personals.
PUBLIC HEALTH RELEVANCE: This application has significant relevance to the purpose of the PA-07-089. Using both in vitro infection and ex vivo models, this project will study for the first time the production and gene expression of neuropathogenic molecules associated with HIV-1B and HIV-C infection. Identification of the mechanisms of clade specific neuropathogenesis will help to design novel strategies to prevent neuropathogenesis in HIV infected subjects and can induce cross-clade antiviral immune response against multiclade or recombinant pandemic HIV-1 infection that is currently facing the world including United States.
描述(由申请人提供):在美国和西方世界发现的主要HIV-1亚型是进化枝B,与撒哈拉以南非洲和亚洲存在的进化枝C显著不同。据估计,在大约3320万感染HIV-1的人中,大约60%的感染是单独的进化枝C,HIV-1C感染正在迅速蔓延到世界其他地区。艾滋病常伴有神经病理异常。目前对HIV-1神经发病机制的认识来自美国和西方国家的B进化枝,而关于C进化枝的神经发病机制的信息很少。我们假设进化枝B和C对中枢神经系统细胞产生不同的作用,导致不同的神经发病机制,并且该机制可能是由有丝分裂原活化蛋白(MAP)激酶信号转导途径的失调介导的。因此,我们将首次研究:(目的#1a)用进化枝B和C病毒体外感染对原代单核细胞和CNS细胞(星形胶质细胞、小胶质细胞)的促炎细胞因子(TNF 1和IL-6)、趋化因子(MCP-1和RANTES)和神经毒素(IDO)的产生和基因表达的影响,并检查(目的#1 B)进化枝特异性病毒感染诱导的差异失调机制是否由丝裂原活化蛋白(MAP)激酶信号转导途径的调节介导。此外,这些体外感染研究将与离体研究(目标#2)进行比较、关联和补充,离体研究使用来自迈阿密研究的HIV-1B感染受试者和印度合作研究所研究的HIV-1C感染受试者的单核细胞。这些研究的结果可能a)揭示了进化枝特异性感染对神经发病机制的不同影响,B)帮助开发治疗上有用的药剂,其可以减弱或预防与进化枝特异性HIV-1感染相关的神经发病机制,和c)设计新的策略以开发预防性和治疗性全局疫苗,其可以诱导针对多进化枝或重组大流行性HIV-1的跨进化枝抗病毒免疫应答。1感染,目前面临的世界,包括美国,其中非B亚型最近已报告在移民人口和我们的军事人员。
公共卫生相关性:本申请与PA-07-089的目的具有显著相关性。利用体外感染和离体模型,该项目将首次研究与HIV-1B和HIV-C感染相关的神经致病分子的产生和基因表达。确定进化枝特异性神经发病机制将有助于设计新的策略来预防HIV感染受试者的神经发病,并且可以诱导针对包括美国在内的世界目前面临的多进化枝或重组大流行HIV-1感染的跨进化枝抗病毒免疫应答。
项目成果
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科研奖励数量(0)
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MADHAVAN P. NAIR其他文献
MADHAVAN P. NAIR的其他文献
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