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（由适用提供）：在急性HIV/SIV期间，在肠道相关的淋巴组织组织（GALT）中，CD4+ T细胞的大量部署在慢性感染期间持续持续的CD4+ T细胞损失会导致对Galt和上层的粘膜上皮造成逐渐损害。这些事件会导致免疫功能障碍，病毒载荷和疾病进展的速度随着时间的流逝。 CD4+ T细胞通过GALT中产生的信号传输到GALT，其中包括视黄酸的释放，进而导致α4ß7整合蛋白和CCR9在细胞表面上的上调。通过与肠壁上的上皮细胞表达的同源受体madcam和CCL25相互作用，通过与肠壁上的上皮细胞相互作用，将表达α4ß7和CCR9的细胞选择性地为galt。最近的数据表明，除了充当归因受体外，α4ß7还可以作为许多HIV和SIV菌株的替代受体，其V1/V2 ENV段对α4ß7具有与MadCam相似的自然配体的“基序”。此外，位于V1/V2和V3/C4 ENV区域的序列包含残留物，如果脱糖基化，它们显着增强了病毒与结合α4ß7的亲和力。这种α4ß7高亲和力HIV-1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，引发抗抗α4ß7MAB的给药可显着降低GALT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。 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对GALT病毒血症的更有效和长期控制； 2）定义肠道组织的组织病理学分析，重点是描述蛋白质在维持肠道组织完整性中所涉及的作用，定义细菌易位的动力学和肠道渗透性的生理测量； 3）确定α4ß7影响其效果的机制a）通过阻止α4ß7的受体功能或通过使用重新组合重复效应的重组效应α44的α44β效应α44β74的运输来确定α4ß7mAb是否通过阻断α4ß7的受体功能来介导其效应，或通过阻断α4ß7表达细胞的效果。使用W.T.和重组ENV糖基化的Shiv的含量较低的α4ß7与低v/s高亲和力结合，C）通过使用α4ß7结合α4ß7的影响受到ENV糖基化水平的影响。意识到有效的艾滋病毒疫苗不仅需要引起广泛的中和中和特定病毒特异性CTL，而且还意味着防止与疾病进展密切相关的galt损伤，还强调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