Analysis of human uterine mucosal cells as targets of HIV-1 infection
人类子宫粘膜细胞作为 HIV-1 感染靶点的分析
基本信息
- 批准号:8925576
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-10-01 至 2018-09-30
- 项目状态:已结题
- 来源:
- 关键词:AIDS preventionAIDS/HIV problemAccountingAcquired Immunodeficiency SyndromeAddressAffectAutologousBasic ScienceCCR5 geneCD4 Positive T LymphocytesCaringCell modelCellsCervix MucusChronicClinical TreatmentDataEducational workshopEndometrialEndometriumEnvironmentEpithelial CellsEpitheliumFemaleGenomeGonadal Steroid HormonesHIVHIV ReceptorsHIV-1HealthHeterosexualsHumanHuman ResourcesImmunologicsIndividualInfectionLaboratoriesLamina PropriaLengthLuteal PhaseMediatingMenstrual cycleMicrospheresModalityModelingMolecular CloningMolecular VirologyMucosal ImmunityMucous MembranePathogenesisPathway interactionsPatient CarePredispositionPreventionPrevention ResearchPropertyRecording of previous eventsReporterResearchResearch PriorityResearch Project GrantsResearch ProposalsRiskRouteSample SizeSeminal fluidSensitivity and SpecificityServicesSiteSourceStagingT-LymphocyteTestingTimeUnited States National Institutes of HealthUterusVaccinesVeteransViralVirionVirusVirus DiseasesWomanWomen&aposs Healthanalytical methodfitnesshealth administrationinnate immune functioninnovationmalemicrobicidemyometriumpandemic diseasepathogenprogramspublic health relevancereceptorreproductive tractresearch studysperm celltooltranscytosistransmission processtreatment trialvirus host interaction
项目摘要
DESCRIPTION (provided by applicant):
HIV/AIDS is a significant health risk to both male and female veterans, and is transmitted predominantly by heterosexual intercourse. A roadblock to the discovery of efficacious prevention modalities, including vaccines and microbicides, is the incomplete understanding of basic virus-host interactions that underlie the acquisition of mucosal HIV-1 infection in the female genital tract. Two recent NIH workshops on Mucosal Immunity and HIV Prevention highlighted under-explored fundamental questions that need to be addressed, including anatomical sites of early virus infection in the female reproductive tract (FRT), and the influence
of endogenous sex hormones on the mucosal environment and susceptibility to HIV-1. We submit that the endometrial mucosa of the uterus constitutes a site of early HIV-1 infection. (i) The upper FRT (uFRT) is accessible to pathogens. The uterus is readily accessible to sperm, experimental microspheres, viral and bacterial pathogens, and possibly HIV-1 virions attached to sperm. (ii) The cervical mucus is an imperfect barrier and upward myometrium contractions likely promote delivery of semen content into the uFRT. (iii) The uFRT comprises an abundance of HIV-1 target cells beneath the epithelium lining. (iv) Cellular and innate immune functions in the uFRT are suppressed during the secretory phase of the menstrual cycle. (v) Previous studies on HIV-1 infection of UEC are. (vi) Innovative and transformative virologic strategies are available in our laboratory that will facilitate physiologically relevant studies using primary mucosal transmission models, including transmitted/founder (T/F) HIV-1 infectious molecular clones (IMC), and HIV- 1 "reporter genomes" that augment both sensitivity and specificity for dissecting early virus-host mucosal interactions. (vii) We present preliminary results that to our knowledge demonstrate for the first time UEC are susceptible to infection by T/F. Therefore, there exists essential virologic underpinnings and compelling rationale to further examine the uFRT as a potential site for the acquisition of mucosal HIV-1 infection and transmission. Our central hypothesis is that the uFRT mucosa is vulnerable to productive T/F HIV-1 infection. To test this hypothesis, we propose the following specific aims: (1) To determine the susceptibility of primary UEC to productive infection by T/F, chronic control and laboratory strains of HIV-1. Viruses expressing T/F envs from isogenic reporter proviral genomes will be studied, enabling sensitive and specific analyses of productive HIV-1 infection in a primary UEC model of virus infection. Importantly, chronic control viruses will be analyzed in parallel experiments to rigorously address the question of whether T/F viruses possess unique fitness properties for infecting potential target cells that exist in the uFRT mucosa. (2) To elucidate cis and trans infection pathways by which T/F HIV-1 spreads from primary UEC to endometrial CD4+ T lymphocytes. Mucosal CD4+ T cells isolated from endometrium will first be analyzed for their susceptibility to infection by T/F and control viruses to establish important underpinnings for subsequent experiments with UEC. The following experiments will elucidate susceptibilities of autologous CD4+ T cells to HIV-1 infection mediated by de novo produced virus from infected UEC or transcytosis of intact/infectious virus particles. The results will be analyzed to elucidate
virus subtype- and strain-specific susceptibilities of UEC and CD4+ T lymphocytes to HIV-1 infection, and identify mechanisms/pathways of virus entry and correlations of these factors with menstrual cycle stage. Such findings promise to provide critical underpinnings for translational prevention research initiatives.
描述(由申请人提供):
艾滋病毒/艾滋病对男性和女性退伍军人来说都是一个重大的健康风险,并且主要通过异性性交传播,发现有效预防方法(包括疫苗和杀微生物剂)的一个障碍是对基本病毒与宿主相互作用的了解不完全。女性生殖道粘膜 HIV-1 感染的发生最近两次 NIH 关于粘膜免疫和 HIV 预防的研讨会强调了需要解决的尚未充分探索的基本问题,包括生殖道的解剖部位。女性生殖道(FRT)早期病毒感染及其影响
内源性激素对粘膜环境和 HIV-1 易感性的影响 我们认为子宫内膜粘膜是早期 HIV-1 感染的部位。精子、实验微球、病毒和细菌病原体以及可能附着在精子上的 HIV-1 病毒颗粒很容易接触到 (ii) 宫颈粘液是一个不完善的屏障,向上。子宫肌层收缩可能促进精液内容物输送到 uFRT 中 (iii) uFRT 在上皮层下方包含大量的 HIV-1 靶细胞 (iv) uFRT 中的细胞和先天免疫功能在分泌阶段受到抑制。 (v) 先前关于 UEC 的 HIV-1 感染的研究是 (vi) 我们的实验室提供了创新和变革性的病毒学策略,这将促进使用初级的生理相关研究。粘膜传播模型,包括传播/创建者 (T/F) HIV-1 感染性分子克隆 (IMC) 和 HIV-1“报告基因组”,可增强剖析早期病毒与宿主粘膜相互作用的敏感性和特异性 (vii) 我们。据我们所知,初步结果首次证明 UEC 容易受到 T/F 感染,因此,存在必要的病毒学基础和令人信服的理由来进一步检查 uFRT 作为潜在的感染部位。我们的中心假设是 uFRT 粘膜容易受到生产性 T/F HIV-1 感染的影响。为了检验这一假设,我们提出以下具体目标:(1)确定原发性的易感性。将研究从同基因报告原病毒基因组表达 T/F envs 的 T/F、慢性对照和实验室病毒对 UEC 的生产性感染,从而能够对原发性 HIV-1 感染进行灵敏和特异性的分析。重要的是,将在平行实验中分析慢性对照病毒,以严格解决 T/F 病毒是否具有感染 uFRT 粘膜中存在的潜在靶细胞的独特适应性的问题 (2) 阐明顺式。首先分析从子宫内膜分离的粘膜 CD4+ T 细胞的易感性。 T/F 和对照病毒感染,为随后的 UEC 实验奠定重要基础。以下实验将阐明自体 CD4+ T 细胞对感染 UEC 的从头产生的病毒或完整/感染性病毒转胞吞作用介导的 HIV-1 感染的敏感性。将对结果进行分析以阐明。
UEC 和 CD4+ T 淋巴细胞对 HIV-1 感染的病毒亚型和毒株特异性敏感性,并确定病毒进入的机制/途径以及这些因素与月经周期阶段的相关性,这些发现有望为转化预防研究举措提供重要基础。 。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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JOHN Christopher KAPPES其他文献
JOHN Christopher KAPPES的其他文献
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{{ truncateString('JOHN Christopher KAPPES', 18)}}的其他基金
The effects of masculinizing gender-affirming hormone therapy for transgender men on susceptibility to HIV-1 infection modelled ex vivo in cervical mucosal tissue
跨性别男性男性化性别肯定激素治疗对子宫颈粘膜组织离体 HIV-1 感染易感性的影响
- 批准号:
10748946 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Elucidating mechanisms of HIV-1 mucosal transmission
阐明 HIV-1 粘膜传播机制
- 批准号:
10553626 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Elucidating mechanisms of HIV-1 mucosal transmission
阐明 HIV-1 粘膜传播机制
- 批准号:
10428455 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Elucidating mechanisms of HIV-1 mucosal transmission
阐明 HIV-1 粘膜传播机制
- 批准号:
9892706 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Single cycle reporter assay for quantifying HIV-1 Nab
用于量化 HIV-1 Nab 的单循环报告基因检测
- 批准号:
6694007 - 财政年份:2003
- 资助金额:
-- - 项目类别:
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