Modulating mucosal DCs and T cells to limit SIV spread
调节粘膜 DC 和 T 细胞以限制 SIV 传播
基本信息
- 批准号:8889591
- 负责人:
- 金额:$ 94.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-07-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAntiviral ResponseArtsAttenuatedBiologyBloodCCR5 geneCD4 Positive T LymphocytesCell physiologyCellsClinicalCoculture TechniquesDataDendritic CellsDendritic cell activationDisease ProgressionDouble-Stranded RNAEnvironmentEventFlow CytometryFosteringFunctional disorderGrowthHIVHIV Envelope Protein gp120HIV InfectionsHuman Herpesvirus 2ImmuneImmunityIn VitroInfectionInfection ControlInstructionInterferonsLeukocytesMacacaMeasuresMediatingMethodsMicroscopyModelingMolecularMucous MembraneNatural ImmunityPopulationPredispositionRecruitment ActivityRegulatory T-LymphocyteResearchRoleSIVSignal PathwaySimplexvirusSiteStagingSystemT-LymphocyteTestingTimeTissuesViralVirusVirus DiseasesVirus ReplicationWorkadaptive immunityanalogbasecellular targetingchemokinecytokineimmune activationimmune functionin vivoinhibitor/antagonistlymph nodesnovelpathogenpreventprotective effectrectalresponsesexual HIV transmissiontooltranscription factortransmission process
项目摘要
Dendritic cells (DCs) have been (i) implicated, along with T cells, as one of the first leukocytes targeted by
HIV after mucosal exposure and (ii) shown to transmit virus efficiently to CD4* T cells: direct transfer of
captured/internalized virus (immature and mature DCs) and transfer of newly synthesized virus (immature
DCs, iDCs). The SIV-macaque model is a precious tool to study the role of DCs in HIV transmission and
disease progression. The DC-T cell milieu provides a distinctive niche in which SIV/HIV can propagate in
vitro and in vivo, with different subsets of DCs and T cells influencing the level of virus growth. Wild type (wrt)
vs ne/-defective {Anef) virus replication is dependent on the state of activation of the DC: wt overcomes the
limitations of IDCs to foster infection in the DC-T cell milieu. In vivo Anef infection of macaques affords
protection against wt infection, suggesting that in the absence of /7ef stronger effector immunity is mounted.
In addition, HSV-2 infection augments HIV transmission possibly through the persistence of increased
numbers of HIV target cells within the tissues and down-modulation of DC immunostimulatory capacity. But
the exact mechanisms of such remain unclear. Within this new 5-year proposal we are expanding our current
research to delve more deeply into this biology in order to define these early events in HIV transmission. This
will be achieved through two new Specific Aims. Specifically, we hypothesize that HSV-2 enhances DCdriven
HIV infection by initially increasing the numbers of highly susceptible a4/J7'^'^''CD4* T cells in the
earliest stages of infection, as well as dampening overall effective immunity (reduced DC function, increased
Tregs). Conversely, DC activation via poly(IC) (a synthetic analog of dsRNA) shuts down HIV/SIV replication.
We believe that this might be due (at least in part) to the "proper" activation of DCs resulting in the triggering
of important innate (e.g.. APOBEC) and adaptive responses that limit HIV/SIV spread. By studying wt and
4rtef infections we plan to delineate the role of iDCs and T cells (a4p7'^'^'^CD4'' T cells and Tregs) in mucosal
transmission. We propose that the down-modulation of DC function by HSV-2 will enhance iDC-a4/J7'"^'' T
cell and IDC-Treg involvement even in Anef infection, while poly(lC) wilt limit HIV/SIV (and HSV-2) replication
and augment anti-viral immunity (increased DC activation, fewer a4l3f'^'^CD4* T cells). Identifying the
molecular requirements for virus transmission and the innate and adaptive responses that coincide with virus
control will provide new targets for novel blocking strategies.
树突状细胞(DC)已经(i)与T细胞一起沿着被认为是由T细胞靶向的第一批白细胞之一。
粘膜暴露后的HIV和(ii)显示出有效地将病毒传播到CD 4 * T细胞:
捕获/内化的病毒(未成熟和成熟DC)和转移新合成的病毒(未成熟
DC、iDC)。SIV-猕猴模型是研究DC在HIV传播中的作用的宝贵工具,
疾病进展。DC-T细胞环境提供了一个独特的小生境,SIV/HIV可以在其中繁殖。
体外和体内,不同的DC和T细胞亚群影响病毒生长水平。野生型(WRT)
vs nef缺陷型(Anef)病毒复制依赖于DC的激活状态:wt克服了DC的激活。
IDC在DC-T细胞环境中促进感染的局限性。猕猴的体内Anef感染提供了
针对WT感染的保护,这表明在没有β EF的情况下,获得了更强的效应免疫。
此外,HSV-2感染可能通过持续增加HIV-1感染而增加HIV-1的传播。
组织内HIV靶细胞的数量和DC免疫刺激能力的下调。但
其确切机制尚不清楚。在这个新的5年计划中,我们正在扩大我们目前的
研究更深入地研究这种生物学,以确定艾滋病毒传播的早期事件。这
将通过两个新的具体目标来实现。具体来说,我们假设HSV-2增强了DC驱动的
HIV感染通过最初增加高敏感性a4/J7“^"^”CD 4 * T细胞的数量来实现。
感染的最早阶段,以及抑制整体有效免疫(DC功能降低,
Tennis)。相反,通过poly(IC)(dsRNA的合成类似物)激活DC会关闭HIV/SIV复制。
我们认为,这可能是由于(至少部分)DC的“适当”激活导致触发
重要的先天(例如,APOBEC)和限制HIV/SIV传播的适应性反应。通过研究WT和
我们计划描述iDC和T细胞(a4 p7 + CD 4 + T细胞和T细胞)在粘膜感染中的作用。
传输我们提出HSV-2对DC功能的下调将增强iDC-a4/J7“”^“T
细胞和IDC-Treg参与,即使在Anef感染,而聚(IC)将限制HIV/SIV(和HSV-2)的复制
并增强抗病毒免疫力(增加的DC活化,更少的α 4/3 β-CD 4 + T细胞)。识别
病毒传播的分子要求以及与病毒传播相一致的先天性和适应性反应
控制将为新的阻断策略提供新的靶点。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Simian immunodeficiency virus interactions with macaque dendritic cells.
猿猴免疫缺陷病毒与猕猴树突状细胞的相互作用。
- DOI:10.1007/978-1-4614-4433-6_6
- 发表时间:2013
- 期刊:
- 影响因子:0
- 作者:Teleshova,Natalia;Derby,Nina;Martinelli,Elena;Pugach,Pavel;Calenda,Giulia;Robbiani,Melissa
- 通讯作者:Robbiani,Melissa
Attachment and fusion inhibitors potently prevent dendritic cell-driven HIV infection.
附着和融合抑制剂有效防止树突状细胞驱动的HIV感染。
- DOI:10.1097/qai.0b013e3181ff2aa5
- 发表时间:2011-03-01
- 期刊:
- 影响因子:0
- 作者:Frank I;Robbiani M
- 通讯作者:Robbiani M
The frequency of α₄β₇(high) memory CD4⁺ T cells correlates with susceptibility to rectal simian immunodeficiency virus infection.
- DOI:10.1097/qai.0b013e31829f6e1a
- 发表时间:2013-12-01
- 期刊:
- 影响因子:0
- 作者:Martinelli E;Veglia F;Goode D;Guerra-Perez N;Aravantinou M;Arthos J;Piatak M Jr;Lifson JD;Blanchard J;Gettie A;Robbiani M
- 通讯作者:Robbiani M
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Nina R. Derby其他文献
Nina R. Derby的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Nina R. Derby', 18)}}的其他基金
An Etonogestrel/Ethinyl Estradiol/QGriffithsin (ETG/EE/QGRFT) IVR to Prevent Pregnancy and HIV
用于预防怀孕和艾滋病毒的依托孕烯/乙炔雌二醇/QGriffithsin (ETG/EE/QGRFT) IVR
- 批准号:
10394426 - 财政年份:2020
- 资助金额:
$ 94.54万 - 项目类别:
An Etonogestrel/Ethinyl Estradiol/QGriffithsin (ETG/EE/QGRFT) IVR to Prevent Pregnancy and HIV
用于预防怀孕和艾滋病毒的依托孕烯/乙炔雌二醇/QGriffithsin (ETG/EE/QGRFT) IVR
- 批准号:
9926449 - 财政年份:2020
- 资助金额:
$ 94.54万 - 项目类别:
An Etonogestrel/Ethinyl Estradiol/QGriffithsin (ETG/EE/QGRFT) IVR to Prevent Pregnancy and HIV
用于预防怀孕和艾滋病毒的依托孕烯/乙炔雌二醇/QGriffithsin (ETG/EE/QGRFT) IVR
- 批准号:
10600151 - 财政年份:2020
- 资助金额:
$ 94.54万 - 项目类别:
Modulating mucosal DCs and T cells to limit SIV spread
调节粘膜 DC 和 T 细胞以限制 SIV 传播
- 批准号:
8702072 - 财政年份:1997
- 资助金额:
$ 94.54万 - 项目类别:
Modulating mucosal DCs and T cells to limit SIV spread
调节粘膜 DC 和 T 细胞以限制 SIV 传播
- 批准号:
9102863 - 财政年份:1997
- 资助金额:
$ 94.54万 - 项目类别:
相似海外基金
Regulation of RIG-I mediated antiviral response upon influenza A virus infection
RIG-I介导的甲型流感病毒感染抗病毒反应的调节
- 批准号:
494286 - 财政年份:2023
- 资助金额:
$ 94.54万 - 项目类别:
Operating Grants
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法
- 批准号:
10364056 - 财政年份:2022
- 资助金额:
$ 94.54万 - 项目类别:
ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
- 批准号:
10621913 - 财政年份:2022
- 资助金额:
$ 94.54万 - 项目类别:
ADAR1-mediated antiviral response in Zika virus (ZIKV) infection
ADAR1 介导的寨卡病毒 (ZIKV) 感染抗病毒反应
- 批准号:
10373627 - 财政年份:2022
- 资助金额:
$ 94.54万 - 项目类别:
Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy
激活 DNA-PK 依赖性抗病毒反应作为一种新型癌症免疫疗法
- 批准号:
10553146 - 财政年份:2022
- 资助金额:
$ 94.54万 - 项目类别:
Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways
IgE介导的单核细胞抗病毒反应途径的调节机制
- 批准号:
10640247 - 财政年份:2021
- 资助金额:
$ 94.54万 - 项目类别:
Interplay between AMPK and Hippo Signaling Regulates Ocular Antiviral Response to Zika virus infection
AMPK 和 Hippo 信号传导之间的相互作用调节眼部对寨卡病毒感染的抗病毒反应
- 批准号:
10322026 - 财政年份:2021
- 资助金额:
$ 94.54万 - 项目类别:
Mechanisms of IgE-mediated regulation of monocyte antiviral response pathways
IgE 介导的单核细胞抗病毒反应途径调节机制
- 批准号:
10438876 - 财政年份:2021
- 资助金额:
$ 94.54万 - 项目类别:
Antiviral response coupled with transposon derepression in Alzheimer's disease and aging
抗病毒反应与转座子去抑制在阿尔茨海默病和衰老中的作用
- 批准号:
10629440 - 财政年份:2021
- 资助金额:
$ 94.54万 - 项目类别:
Epigenetic Control of Mucosal IRF1/IFN-III Antiviral Response by Enhancer-like Promoter and its Coding lncRNA
增强子样启动子及其编码lncRNA对粘膜IRF1/IFN-III抗病毒反应的表观遗传控制
- 批准号:
10373575 - 财政年份:2021
- 资助金额:
$ 94.54万 - 项目类别: