Gut Homing Cells in SIV infection

SIV 感染中的肠道归巢细胞

• 批准号: 8469822
• 负责人: Aftab A. Ansari
• 金额: $ 126.27万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469822
• 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; Image; 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; absorption; adaptive immunity; base; compare effectiveness; env Gene Products; env Glycoproteins; experience; follow-up; glycosylation; in vivo; inhibitor/antagonist; mortality; mutant; new technology; nonhuman primate; novel; prevent; protective effect; receptor; receptor function; rectal; simian human immunodeficiency virus; small molecule; 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 ?4?7 integrin and CCR9 on the cell surface. Cells expressing ?4?7 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 ?4?7, 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 ?4?7 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 ?4?7. Such ?4?7 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??4?7 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 ?4?7 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 ?4?7 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 ?4?7 induces its effect a) by determining whether ?4?7 mAb mediates its effect via blocking the receptor function of the ?4?7 or by blocking the trafficking of ?4?7 expressing cells by using recombinant replication competent SIV env constructs that do or do not bind ?4?7, b) by determining whether the in vivo effect of anti-??4?7 treatment is influenced by the level of env glycosylation using W.T. & recombinant env deglycosylated SHIV's that bind ?4?7 with low v/s high affinity, c) determine the tissue/organ localization of virus and CD4+ cells in the control and ?4?7 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 内产生的信号运输至 GALT，其中包括视黄酸的释放，进而导致细胞表面上的 α4β7 整联蛋白和 CCR9 上调。表达 ?4?7 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。最近的数据表明，α4β7 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 其天然配体的 α4β7 识别“基序”。此外，位于V1/V2和V3/C4 env区的序列含有残基，如果这些残基被去糖基化，则显着增强病毒结合α4β7的亲和力。这种α4β7高亲和力结合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 感染之前和期间施用灵长类抗 4?7 mAb，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 ?4?7 给药是否能有效降低动物中的 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) 阴道内低重复剂量感染以模拟自然传播，以及 d) 单独使用 CCR9 的小分子抑制剂或与 ?4?7 mAb 联合给药是否会更有效 以及长期控制 GALT 病毒血症； 2）定义肠道组织的组织病理学分析，重点是描述维持肠道组织完整性的蛋白质的作用，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 α4β7 诱导其效应所涉及的机制 a) 通过确定 4β7 mAb 是否通过阻断 α4β7 的受体功能或通过使用结合或不结合 α4β7 的重组复制能力 SIV env 构建体阻断 α4β7 表达细胞的运输来介导其效应，b) 通过确定抗 α4β7 治疗的体内效应是否受到影响 通过使用 W.T. 和以低 v/s 高亲和力结合 ?4?7 的重组 env 去糖基化 SHIV 的 env 糖基化水平，c) 使用我们实验室开发的新优化的实时“LIVE”PET-CT 扫描技术确定对照和 ?4?7 施用动物中病毒和 CD4+ 细胞的组织/器官定位。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，这一认识凸显了这些研究的重要性。