Gut Homing Cells in SIV infection
SIV 感染中的肠道归巢细胞
基本信息
- 批准号:9052112
- 负责人:
- 金额:$ 142.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-05-17 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAcuteAffinityAnimalsAntiviral AgentsBindingBiological AssayBloodCCL25 geneCCR9 geneCD4 Lymphocyte CountCD4 Positive T LymphocytesCell LineCell LineageCell surfaceCellsCellular StructuresChronicClinicalDataDiseaseDisease ProgressionDoseDrug or chemical Tissue DistributionEpithelialEpithelial CellsEpitheliumEventGPR-9-6 receptorGastrointestinal tract structureGut associated lymphoid tissueHIVHIV InfectionsHIV vaccineHIV-1HematopoieticHome environmentHomingImaging TechniquesImmuneImmune System DiseasesImmune responseImmunohistochemistryImmunologyIn Situ HybridizationIncidenceInfectionInjuryIntegrinsIntestinesIntravenousKineticsLifeLigandsLymphocyteMacacaMacaca mulattaMeasurementMediatingMonitorMonkeysMonoclonal AntibodiesMorbidity - disease rateNatural ImmunityOrganPET/CT scanPathogenesisPathologyPermeabilityPhysiologicalPlasmaProteinsRecombinantsReportingResearchResearch PersonnelRoleRouteSIVSignal TransductionSymptomsTechniquesTestingTherapeuticTherapeutic EffectTight JunctionsTimeTissuesTretinoinUp-RegulationVaccinesViralViral Load resultViremiaVirusVirus Replicationabsorptionadaptive immunitybasecompare effectivenessenv Gene Productsenv Glycoproteinsexperiencefollow-upglycosylationin vivoin vivo imaginginhibitor/antagonistmortalitymutantnew technologynonhuman primatenovelpreventprotective effectreceptorreceptor functionrectalsimian human immunodeficiency virussmall moleculesmall molecule inhibitorsugartooltraffickingtransmission processviral DNAviral RNA
项目摘要
DESCRIPTION (provided by applicant): The massive depletion of CD4+ T cells within the gut associated lymphoid tissues (GALT) during acute HIV/SIV followed by sustained CD4+ T cell loss during chronic infection leads to progressive damage to the GALT and the overlying mucosal epithelium. These events contribute to immune dysfunction, viral loads and the rate of disease progression over time. The CD4+ T cells traffic to the GALT by signals generated within the GALT which include the release of retinoic acid which in turn leads to upregulation of the α4ß7 integrin and CCR9 on the cell surface. Cells expressing α4ß7 and CCR9 selectively home to the GALT by interacting with their cognate receptors MAdCAM and CCL25 expressed by epithelial cells lining the intestinal wall. Recent data show that α4ß7, besides serving as the homing receptor, also serves as an alternate receptor for many strains of HIV and SIV whose V1/V2 env segments have recognition 'motifs' for α4ß7 similar to MAdCAM its natural ligand. In addition, sequences localized to the V1/V2 and V3/C4 env region contain residues which, if deglycosylated, markedly enhance the affinity of the virus to bind α4ß7. Such α4ß7 high affinity binding HIV-1 is thought to be preferentially transmitted via the mucosal route. Our lab has recently shown that the administration of a primatized anti-α4ß7 mAb, just prior to and during acute IV and intra-rectal SIV infection, leads to markedly reduced viral loads in the GALT and provides, for the first time, tools to examine in detail the events that occur during acute infection. The studies proposed herein are aimed at: 1) determining the clinical utility of these previous findings by determining if α4ß7 administration is effective in lowering GALT viral loads in animals a) infected intravaginally, b) post SIV infection, c) infected with low repeated doses intravaginally to mimic natural transmission, and d) if a small molecule inhibitor of CCR9 alone or with α4ß7 mAb administration leads to more effective and prolonged control of GALT viremia; 2) defining the histopathological analysis of the gut tissues with a focus on delineating the role of proteins involved in maintaining gut tissue integrity, defining the kinetics of bacteril translocation and the physiologic measurement of gut tissue permeability; and 3) determining the mechanisms involved by which α4ß7 induces its effect a) by determining whether α4ß7 mAb mediates its effect via blocking the receptor function of the α4ß7 or by blocking the trafficking of α4ß7 expressing cells by using recombinant replication competent SIV env constructs that do or do not bind α4ß7, b) by determining whether the in vivo effect of anti-α4ß7 treatment is influenced by the level of env glycosylation using W.T. & recombinant env deglycosylated SHIV's that bind α4ß7 with low v/s high affinity, c) determine the tissue/organ localization of virus and CD4+ cells in the control and α4ß7 administered animals using a newly optimized real time "LIVE" PET-CT scanning technique developed by our lab. The realization that effective HIV vaccines require to elicit not only broad neutralizing Abs and effective virus specific CTL's but also means to prevent GALT injury which is intimately associated with disease progression, highlight the importance of these studies.
描述(由申请人提供):在急性 HIV/SIV 期间,肠道相关淋巴组织 (GALT) 内 CD4+ T 细胞大量耗竭,随后在慢性感染期间持续 CD4+ T 细胞损失,导致 GALT 和上覆粘膜上皮进行性损伤随着时间的推移,这些事件会导致免疫功能障碍、病毒载量和疾病进展速度。CD4+ T 细胞通过 GALT 内产生的信号(包括释放)转运至 GALT。最近的数据显示,表达 α4ß7 和 CCR9 的细胞通过与肠壁上皮细胞表达的同源受体 MAdCAM 和 CCL25 相互作用,选择性地归巢到 GALT。 α4ß7 除了充当归巢受体外,还充当许多 HIV 和 SIV 毒株的替代受体,其V1/V2 env 片段具有类似于 MAdCAM 天然配体的 α4ß7 识别“基序”。此外,位于 V1/V2 和 V3/C4 env 区域的序列含有残基,如果去糖基化,可显着增强病毒与病毒的亲和力。结合 α4ß7。这种 α4ß7 高亲和力结合 HIV-1 被认为优先通过粘膜途径传播。灵长类化抗 α4ß7 mAb 在急性 IV 和直肠内 SIV 感染之前和期间,可显着降低 GALT 中的病毒载量,并首次提供了详细检查急性感染期间发生的事件的工具。本文提出的研究旨在:1) 通过确定 α4ß7 给药是否能有效降低动物 a) 阴道内感染,b) SIV 感染后,c) 确定这些先前发现的临床实用性阴道内低重复剂量感染以模拟自然传播,d) 单独使用 CCR9 小分子抑制剂或与 α4ß7 mAb 联合使用是否可以更有效、更长时间地控制 GALT 病毒血症;2) 通过重点描述蛋白质在维持肠道组织完整性中的作用,定义细菌易位的动力学和肠道组织渗透性的生理测量;3) 确定相关机制; α4ß7 诱导其效应 a) 通过确定 α4ß7 mAb 是否通过阻断 α4ß7 的受体功能或通过使用结合或不结合 α4ß7 的重组复制能力 SIV env 构建体来阻断 α4ß7 表达细胞的运输来介导其效应,b)通过使用 W.T. 和重组体确定抗 α4ß7 治疗的体内效果是否受到 env 糖基化水平的影响env 去糖基化 SHIV 以低 v/s 高亲和力结合 α4ß7,c) 使用由我们的实验室意识到,有效的 HIV 疫苗不仅需要引发广泛的中和抗体和有效的病毒特异性 CTL,而且还意味着预防与疾病进展密切相关的 GALT 损伤,这凸显了这些疫苗的重要性。研究。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
MHC and KIR Polymorphisms in Rhesus Macaque SIV Infection.
- DOI:10.3389/fimmu.2015.00540
- 发表时间:2015
- 期刊:
- 影响因子:7.3
- 作者:Walter L;Ansari AA
- 通讯作者:Ansari AA
Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells.
- DOI:10.1186/s12977-015-0185-1
- 发表时间:2015-07-01
- 期刊:
- 影响因子:3.3
- 作者:Tanaka Y;Mizuguchi M;Takahashi Y;Fujii H;Tanaka R;Fukushima T;Tomoyose T;Ansari AA;Nakamura M
- 通讯作者:Nakamura M
Glycosylation of simian immunodeficiency virus influences immune-tissue targeting during primary infection, leading to immunodeficiency or viral control.
猿猴免疫缺陷病毒的糖基化会影响初次感染期间的免疫组织靶向,从而导致免疫缺陷或病毒控制。
- DOI:10.1128/jvi.00948-12
- 发表时间:2012
- 期刊:
- 影响因子:5.4
- 作者:Sugimoto,Chie;Nakamura,Shinichiro;Hagen,ShokoI;Tsunetsugu-Yokota,Yasuko;Villinger,Francois;Ansari,AftabA;Suzuki,Yasuo;Yamamoto,Naoki;Nagai,Yoshiyuki;Picker,LouisJ;Mori,Kazuyasu
- 通讯作者:Mori,Kazuyasu
Phenotypic and Functional Characterization of Monoclonal Antibodies with Specificity for Rhesus Macaque CD200, CD200R and Mincle.
- DOI:10.1371/journal.pone.0140689
- 发表时间:2015
- 期刊:
- 影响因子:3.7
- 作者:Byrareddy SN;Little D;Mayne AE;Villinger F;Ansari AA
- 通讯作者:Ansari AA
Relationship of menstrual cycle and vaginal infection in female rhesus macaques challenged with repeated, low doses of SIVmac251.
- DOI:10.1111/jmp.12177
- 发表时间:2015-10
- 期刊:
- 影响因子:0.7
- 作者:Morris MR;Byrareddy SN;Villinger F;Henning TC;Butler K;Ansari AA;McNicholl JM;Kersh EN
- 通讯作者:Kersh EN
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Aftab A. Ansari其他文献
Virus-induced cytokines regulate circulating lymphocyte levels during primary SIV infections.
病毒诱导的细胞因子在原发性 SIV 感染期间调节循环淋巴细胞水平。
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:4.4
- 作者:
Yvonne J. Rosenberg;Aurelio Cafaro;Terry Brennan;Jack Greenhouse;Francois Villinger;Aftab A. Ansari;Charles C. Brown;Kathy McKinnon;Sharon Bellah;Jacob Yalley;William R. Elkins;Suzanne Gartner;Mark G. Lewis - 通讯作者:
Mark G. Lewis
Hypersensitivity myocarditis in heart transplant candidates.
心脏移植候选人的过敏性心肌炎。
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:0
- 作者:
M. Gravanis;G. Hertzler;R. Franch;L. Stacy;Aftab A. Ansari;Kirk R. Kanter;H. Tazelaar;R. Rodeheffer;C. McGregor - 通讯作者:
C. McGregor
The natural history of disease expression in CD4 and CD8 gene-deleted New Zealand black (NZB) mice.
CD4 和 CD8 基因缺失的新西兰黑 (NZB) 小鼠疾病表达的自然史。
- DOI:
10.4049/jimmunol.157.6.2676 - 发表时间:
1996 - 期刊:
- 影响因子:4.4
- 作者:
S. Chen;Y. Takeoka;Aftab A. Ansari;Richard L. Boyd;Dennis M. Klinman;M. Gershwin - 通讯作者:
M. Gershwin
Aftab A. Ansari的其他文献
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{{ truncateString('Aftab A. Ansari', 18)}}的其他基金
Integrin a4b7 as a predictor of HIV acquisition and pathogenesis
整合素 a4b7 作为 HIV 获得和发病机制的预测因子
- 批准号:
8838886 - 财政年份:2015
- 资助金额:
$ 142.03万 - 项目类别:
THE ANTI-ALPHA-4/BETA-7 MONOCLONAL ANTIBODY PROJECT
抗 ALPHA-4/BETA-7 单克隆抗体项目
- 批准号:
8357511 - 财政年份:2011
- 资助金额:
$ 142.03万 - 项目类别:
ROLE OF VIRUS SPECIFIC IMMUNITY IN PRIMATE MODELS
病毒特异性免疫在灵长类动物模型中的作用
- 批准号:
8357408 - 财政年份:2011
- 资助金额:
$ 142.03万 - 项目类别:
CD4 T CELL ACTIVATION IN SIV INFECTED DISEASE RESISTANT SOOTY MANGABEYS
感染 SIV 的抗病乌白眉猴中 CD4 T 细胞的激活
- 批准号:
8357429 - 财政年份:2011
- 资助金额:
$ 142.03万 - 项目类别:
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