Gut Homing Cells in SIV infection

SIV 感染中的肠道归巢细胞

• 批准号: 9052112
• 负责人: Aftab A. Ansari
• 金额: $ 142.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9052112
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Affinity; Animals; Antiviral Agents; Binding; Biological Assay; Blood; CCL25 gene; CCR9 gene; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cell Line; Cell Lineage; Cell surface; Cells; Cellular Structures; Chronic; Clinical; Data; Disease; Disease Progression; Dose; Drug or chemical Tissue Distribution; Epithelial; Epithelial Cells; Epithelium; Event; GPR-9-6 receptor; Gastrointestinal tract structure; Gut associated lymphoid tissue; HIV; HIV Infections; HIV vaccine; HIV-1; Hematopoietic; Home environment; Homing; Imaging Techniques; Immune; Immune System Diseases; Immune response; Immunohistochemistry; Immunology; In Situ Hybridization; Incidence; Infection; Injury; Integrins; Intestines; Intravenous; Kinetics; Life; Ligands; Lymphocyte; Macaca; Macaca mulatta; Measurement; Mediating; Monitor; Monkeys; Monoclonal Antibodies; Morbidity - disease rate; Natural Immunity; Organ; PET/CT scan; Pathogenesis; Pathology; Permeability; Physiological; Plasma; Proteins; Recombinants; Reporting; Research; Research Personnel; Role; Route; SIV; Signal Transduction; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; Time; Tissues; Tretinoin; Up-Regulation; Vaccines; Viral; Viral Load result; Viremia; Virus; Virus Replication; absorption; adaptive immunity; base; compare effectiveness; env Gene Products; env Glycoproteins; experience; follow-up; glycosylation; in vivo; in vivo imaging; inhibitor/antagonist; mortality; mutant; new technology; nonhuman primate; novel; prevent; protective effect; receptor; receptor function; rectal; simian human immunodeficiency virus; small molecule; small molecule inhibitor; sugar; tool; trafficking; transmission process; viral DNA; viral RNA

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（由申请方提供）：急性HIV/SIV期间肠道相关淋巴组织（GALT）内的CD 4 + T细胞大量耗竭，随后在慢性感染期间持续CD 4 + T细胞丢失，导致GALT和上覆粘膜上皮的进行性损伤。这些事件会导致免疫功能障碍、病毒载量和疾病进展速度。CD 4 + T细胞通过GALT内产生的信号运输至GALT，所述信号包括视黄酸的释放，视黄酸又导致细胞表面上α 4 β 7整联蛋白和CCR 9的上调。表达α 4 β 7和CCR 9的细胞通过与肠壁上皮细胞表达的同源受体MAdCAM和CCL 25相互作用选择性地归巢GALT。最近的数据表明，α 4 β 7除了作为归巢受体外，还作为许多HIV和SIV毒株的替代受体，其V1/V2 env区段具有与MAdCAM其天然配体类似的α 4 β 7识别“基序”。此外，定位于V1/V2和V3/C4 env区的序列含有残基，如果去糖基化，则显著增强病毒结合α 4 β 7的亲和力。这种高亲和力结合HIV-1的α 4 β 7被认为优先通过粘膜途径传播。我们的实验室最近表明，在急性IV和直肠内SIV感染之前和期间给予灵长类抗α 4 β 7 mAb，可显著降低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。本报告提议的研究旨在：1）通过确定α 4 β 7给药是否有效降低动物中的GALT病毒载量来确定这些先前发现的临床效用，a）阴道内感染，B）SIV感染后，c）阴道内以低重复剂量感染以模拟自然传播，和d）如果CCR 9的小分子抑制剂单独或与α 4 β 7 mAb一起给药导致GALT病毒血症的更有效和延长的控制; 2）定义肠组织的组织病理学分析，重点在于描绘参与维持肠组织完整性的蛋白质的作用，确定细菌移位的动力学和肠组织渗透性的生理测量;和3）确定α 4 β 7诱导其作用的机制a）通过确定α 4 β 7 mAb是否通过阻断α 4 β 7的受体功能或通过使用重组可复制SIV env构建体阻断表达α 4 β 7的细胞的运输来介导其作用B）通过使用W.T.和重组env去糖基化的SHIV，其以低v/s高亲和力结合α 4 β 7，c）使用我们实验室开发的新优化的真实的时间“LIVE”PET-CT扫描技术确定对照和施用α 4 β 7的动物中病毒和CD 4+细胞的组织/器官定位。认识到有效的HIV疫苗不仅需要引起广泛的中和抗体和有效的病毒特异性CTL，而且还需要防止与疾病进展密切相关的GALT损伤，突出了这些研究的重要性。

项目成果

MHC and KIR Polymorphisms in Rhesus Macaque SIV Infection.

• DOI: 10.3389/fimmu.2015.00540
• 发表时间: 2015
• 期刊: Frontiers in immunology
• 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: Retrovirology
• 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: Journal of virology
• 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: PloS one
• 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: Journal of medical primatology
• 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