Local Determinants of HSV-2 Shedding in Humans
人类 HSV-2 脱落的局部决定因素
基本信息
- 批准号:7513499
- 负责人:
- 金额:$ 18.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-07-15 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntigensAntiviral AgentsAppearanceAttentionBiological AssayBiopsyBloodCD4 Positive T LymphocytesCD8B1 geneCXCL9 geneCXCR3 geneCell Adhesion MoleculesCell CountCellsClassClinicalCollaborationsCutaneousDNADataDendritic CellsDermalDetectionDrug effect disorderE-SelectinEnzymesExoribonuclease IIFundingGene ExpressionGenesGenital systemHIV-1HealedHeterogeneityHome environmentHomingHumanHuman Herpesvirus 2Human Herpesvirus 4ImmunocompetentIn SituIn VitroIndustryInfectionInfiltrationIntercellular adhesion molecule 1Interferon Type IInterferon Type IIInterferonsInterleukin-15Knockout MiceLeadLesionLeukocytesLigandsLinkLocal TherapyLocalizedLymphocyteLyticMeasuresMediatingMessenger RNAMetabolic Clearance RateModelingMusNatural ImmunityNeuronsNumbersPathogenesisPatientsPatternPersonsPopulationRateRecruitment ActivityRecurrenceReverse Transcriptase Polymerase Chain ReactionRisk FactorsSeveritiesSeverity of illnessSimplexvirusSiteSkinSourceSurfaceT-LymphocyteTestingVaccine DesignWeekWorkbasechemokinechemokine receptorcohortcytokinedaydensitygenital herpeshealinghuman prostaglandin D2 receptorresiquimodselective expressiontransmission process
项目摘要
Recurrent HSV-2 shedding is a major risk factor for HIV-1 transmission. Recent data indicate that HSV-2 is
present up to 40% of days in the periphery. The factors that control HSV-2 shedding in the skin are
incompletely understood. One contributor is likely HSV-2-specific CDS T-cells, which will be studied in
Project 1. This Project will focus on the expression of antiviral genes in the skin and correlating this with
shedding of HSV-2. We hypothesize that a net antiviral state, as measured by the mRNA levels of
interferon-stimulated genes (ISG), will correlate with the re-appearance of HSV-2 DMA after the healing of
symptomatic HSV-2 lesions. Because circulating HSV-2-specific CDS T-cells over-express CXCR3, and
mice with lesions in the CXCR3 axis have accelerated HSV-2 pathogenesis, we further hypothesize that the
CXCR3 ligand chemokines, CXCL9, 10, and 11, will correlate with the infiltration of HSV-2-specific CDS cells
(Project 1) and pDC, and negatively with detection of HSV-2 DMA and mRNA. Plasmacytoid dendritic cells
(pDC) infiltrate HSV-2 lesions in animals and humans (our data), react strongly with HSV-2 via TLR9 to
secrete IFN-a, and are required for defense against HSV-2 in mice. Substantial heterogeneity in pDC
reactivity to HSV-2 has been observed, as have rare patients with pDC numerical or functional deficiencies
and severe HSV infections. pDC likely contribute to the net IFN-driven antiviral state in lesions and the anti-
HSV drug action of resiquimod. We propose blood-based studies to investigate the hypothesis that pDC
number of function correlates with HSV-2 shedding rates, using subjects from the Clinical Core who are
studied in Project I. Aim 1 will correlate ISG and interferon-producing cells with HSV-2 DNA/mRNA
detection in human skin biopsies. Aim 2 will focus on the chemokine receptor utilization of HSV-2-specific
CDS T-cells. Aim 3 will correlate pDC number and function in blood with HSV-2 shedding and clearance
rates. The results may assist in designing vaccines for HSV-2 that elicit cells with the appropriate homing
strategies, and clarify the mechanism of action of innate immunity modifiers as local therapy for HSV-2.
复发性HSV-2脱落是HIV-1传播的主要危险因素。最近的数据表明,HSV-2是
有40%的时间在外围控制HSV-2在皮肤中脱落的因素是
不完全理解。一个贡献者可能是HSV-2特异性CDS T细胞,这将在2015年进行研究。
项目1。本项目将重点研究抗病毒基因在皮肤中的表达,
HSV-2的脱落。我们假设,一个净的抗病毒状态,如测量的mRNA水平,
干扰素刺激基因(ISG),将与HSV-2 DMA的重新出现后,愈合的,
症状性HSV-2病变。因为循环HSV-2特异性CD 8 T细胞过表达CXCR 3,
CXCR 3轴损伤的小鼠加速了HSV-2的发病,我们进一步假设,
CXCR 3配体趋化因子CXCL 9、10和11将与HSV-2特异性CDS细胞的浸润相关
(项目1)和pDC,HSV-2 DNA和mRNA检测呈阴性。浆细胞样树突细胞
(pDC)渗透到动物和人类的HSV-2病变中(我们的数据),通过TLR 9与HSV-2发生强烈反应,
分泌IFN-α,并且是小鼠中防御HSV-2所必需的。pDC中的显著异质性
已经观察到对HSV-2的反应性,如具有pDC数量或功能缺陷的罕见患者
和严重的HSV感染。pDC可能有助于病变中的净IFN驱动的抗病毒状态,而抗IFN-γ可能有助于病变中的抗病毒状态。
瑞喹莫特的HSV药物作用。我们建议基于血液的研究来调查pDC
功能数量与HSV-2排毒率相关,使用来自临床中心的受试者,
在项目I中学习。目的1将ISG和干扰素产生细胞与HSV-2DNA/mRNA的关系进行了研究
在人类皮肤活检中检测到。目的2将集中于HSV-2特异性趋化因子受体的利用
CDS T细胞。目的3将血液中pDC数量和功能与HSV-2脱落和清除相关
rates.这些结果可能有助于设计HSV-2疫苗,以诱导具有适当归巢的细胞
策略,并阐明先天免疫调节剂作为HSV-2局部治疗的作用机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David M Koelle其他文献
David M Koelle的其他文献
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{{ truncateString('David M Koelle', 18)}}的其他基金
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对候选梅毒螺旋体外膜蛋白疫苗抗原的特异性 T 和 B 细胞反应
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