Early Immune Development and Function in Neonates Exposed to Maternal HIV Infection
Early Immune Development and Function in Neonates Exposed to Maternal HIV Infection
批准号:
9973205
负责人:
Huanbin Xu
金额:
$50.47万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-05 至 2022-06-30
关键词:
AIDS preventionAddressAdultAnatomyAntibody FormationAntibody ResponseAntigensArchitectureB cell differentiationB-Lymphocyte SubsetsB-LymphocytesBirthCaringCell CycleCellsChildhood Acute Lymphocytic LeukemiaChronicCommunicationCyclin-Dependent Kinase InhibitorDataDevelopmentEZH2 geneEnvironmentEpigenetic ProcessEventExposure toFetal DevelopmentFrequenciesGene SilencingGenerationsHIVHIV InfectionsHIV-exposed uninfected infantHealthHelper-Inducer T-LymphocyteHepatitis B VirusHistone H3HistopathologyImmuneImmune System DiseasesImmune systemImmunizationImmunization ScheduleImmunologicsImmunologyImpairmentInfantInfectionInflammation MediatorsInflammatoryInfluenza vaccinationInterventionKnowledgeLeukocytesLifeLiquid substanceLymphoidLymphoid CellLymphoid TissueLysineMacacaMaternal-Fetal ExchangeMeasuresModelingMolecularMothersMucous MembraneMyelogenousMyeloid CellsNatural ImmunityNeonatalNewborn InfantOutcomePathogenesisPathologicPlacentaPlasmaPlayPopulationPregnancyPreventionPrimatesPrincipal InvestigatorReactionRegimenRegulatory T-LymphocyteReportingRoleSIVSignal TransductionSterilityStructureStructure of germinal center of lymph nodeSystems DevelopmentTissuesUterusVaccinationVaccinesViral Load resultViral reservoiradaptive immunityantiretroviral therapycomparativecytokinedesignfetalfetal programminghigh riskimmune functionimprovedinhibitor/antagonistlymph nodesneonatal infectionneonatenonhuman primatepathogenprenatal exposureprogramsresponse
中文摘要
首席研究员/项目主任(后、一、中):徐焕斌!
英文摘要
Principal Investigator/Program Director (Last, first, middle): Xu, Huanbin!
PROJECT SUMMARY / ABSTRACT
Maternal HIV infection poses high risks for infecting infants during pregnancy, predisposing abnormalities of
antibody responses to immunization and poor health outcomes in infants, especially during their first year of life,
albeit the majority of newborn infants remain uninfected, suggesting that maternal HIV infection compromises
early immune system development and function. In proposal, we hypothesize that HIV infection during
pregnancy impairs maternal/fetal communications through persistent inflammatory signals and pathological
placenta, which compromise fetal development of systemic and lymphoid tissues, and subsequent antibody
responses to vaccines in early-life. We also hypothesize that administering suppressive combined antiretroviral
therapy (cART) may directly restore fetal immune development, and improve immune function in infants. Using
non-human primate models, we have discovered many unexpected facts regarding the immunology and
pathogenesis of HIV and primate neonatal immunology. We have shown that SIV-infected infants rapidly and
selectively lose mucosal innate lymphoid cells (ILC1/NK, ILC3, ILC17, ILC22) and regulatory T cells resulting in
dysfunctional germinal center (GC) reactions and subsequently, inadequate antibody responses. Our most
recent studies show that normally, GC B cells, rapidly aggregate in follicles within days after birth, highly co-
express Ki67, Bcl-6 and EZH2. However, these EZH2+ GC B cells do not appear in lymph nodes of SIV-
infected neonates, accompanied by impaired lymphoid architecture and inadequate Ab responses. Studies
indicate EZH2 is responsible for epigenetic silencing of the cyclin dependent kinase inhibitor (CDK inhibitor,
cell cycle suppression) via trimethylation of histone H3 lysine 27 (H3K27me3). Here we will investigate the
cellular and molecular mechanisms behind the impaired generation of antibody responses in infants born to
SIV-infected dams through detailed examinations of neonatal and infant mucosal and systemic lymphoid
tissues and their development and function. Given converging data that the growing populations of HIV-
exposed uninfected (HEU) infants have immunologic impairments, it is clear that there are many fundamental
gaps in our understanding of how maternal HIV infection may influence placental function, fetal immune
development, and why HEU infants have defective Ab responses. This proposal is designed to address early
development of systemic and lymphoid compartments in neonates exposed to maternal HIV infection: a)
determining the alterations of placental immunology; b) evaluating neonatal immune development and function
of systemic and lymphoid compartments in the context of maternal HIV infection, and; c) exploring the cellular
and molecular mechanisms involved in compromised Ab responses to routine vaccinations in infants exposed
to maternal HIV infection, with and without short-term cART during pregnancy. The knowledge gained in this
proposal will be of tremendous importance for optimizing HIV prevention, and improving immunization
regimens for infants when exposed to maternal HIV infection.
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会议论文
Early prevention interventions towards ART-free pediatric HIV remission
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批准号:10700531
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项目类别:
-
资助金额:$78.12万
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财政年份:2023
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负责人:Huanbin Xu
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依托单位:
Early Immune Development and Function in Neonates Exposed to Maternal HIV Infection
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批准号:10197795
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项目类别:
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资助金额:$50.05万
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财政年份:2019
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负责人:Huanbin Xu
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依托单位:
Novel strategies for eliminating HIV reservoirs in lymphoid tissues
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批准号:9108374
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项目类别:
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资助金额:$80.94万
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财政年份:2015
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负责人:Huanbin Xu
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依托单位:
Novel strategies for eliminating HIV reservoirs in lymphoid tissues
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批准号:9306087
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项目类别:
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资助金额:$80.44万
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财政年份:2015
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负责人:Huanbin Xu
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依托单位:
海外基金