Gut Homing Cells in SIV infection

SIV 感染中的肠道归巢细胞

• 批准号: 8410467
• 负责人: Aftab A. Ansari
• 金额: $ 132.35万
• 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/8410467
• 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. PUBLIC HEALTH RELEVANCE: Both the HIV/SIV appear to use ?4?7, a molecule expressed by CD4+ T cells as an alternate co- receptor. Our lab has used a monoclonal antibody against the ?4?7 molecule and shown that treatment of monkeys prior to and during the acute intravenous infection period with the monoclonal antibody leads to a marked reduction in viral loads in the gastrointestinal tract. We propose to carry out more detailed studies aimed at defining the clinical use of these initial findings to determine if we can "blunt" the initial gastrointestinal tract pathology which will greatly enhance our understanding of the pathogenic mechanisms involved during acute infection.

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细胞的大量耗竭，然后在慢性感染期间持续持续的CD4+ T细胞损失导致GALT逐渐损害GALT和粘膜上皮上皮。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？4？7整合素和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，将表达？4？7和CCR9的细胞选择性地归为GALT。最近的数据表明，除了充当归巢受体外，还有？4？7还作为许多艾滋病毒和siv菌株的替代受体，其v1/v2 env段的v1/v2 env段对“主题”具有识别为“主题”？此外，位于V1/V2和V3/C4 ENV区域的序列包含残基，如果脱糖，则显着增强了该病毒与结合的亲和力？4？7。如此？4？7高亲和力结合HIV-1被认为是通过粘膜途径传播的。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，施用了启示性的抗?? 4？7 mAb，导致galt中的病毒载量明显降低，并首次提供了详细检查急性感染期间发生的事件的工具。本文提出的研究的目的是：1）确定这些先前发现的临床实用性，通过确定？4？7是否有效地降低动物的Galt病毒载荷有效，a）静脉内感染，b）在静脉内感染，c）静脉内静脉内静电剂量低以模拟自然传播，并有效地降低了ccr的剂量，d）或d）或d）或d）或d）。并长期控制了galt病毒血症； 2）定义对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）确定哪个？4？7的机制诱导其效果a）通过确定？4？7 mab是否通过阻断？4？7 7的受体功能来介导其效应？通过使用W.T.和重组Env糖基化的二糖基化的水平，粘合的SHIV粘合了？4？7具有低v/s高亲和力，c）确定对照中的病毒和CD4+细胞的组织/器官定位，以及？4？4？7 7？7使用新近优化的实时“实时” pet-ct-can-can-can-can-canning技术由我们开发的实验室。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。 公共卫生相关性：HIV/SIV似乎都在使用？4？7，CD4+ T细胞表达的分子作为替代共同受体。我们的实验室使用了针对？4？7分子的单克隆抗体，并表明在急性静脉内感染期之前和期间，猴子对单克隆抗体的治疗导致胃肠道剂中病毒载量显着减少。我们建议进行旨在定义这些初始发现的临床使用的更详细的研究，以确定我们是否可以“钝化”最初的胃肠道病理学，这将大大增强我们对急性感染过程中涉及的致病机制的理解。