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)内的CD4+T细胞大量耗尽，随后在慢性感染期间持续的CD4+T细胞丢失导致GALT和覆盖的粘膜上皮的进行性损害。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内产生的信号运输到GALT，其中包括维甲酸的释放，这反过来又导致细胞表面整合素和CCR9的上调。表达β4、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，选择性地定位于GALT。最近的数据表明，？4？7除了作为归巢受体外，还可以作为许多HIV和SIV毒株的替代受体，其V1/V2包膜片段具有与其天然配体MAdCAM相似的识别？4？7的‘基序’。此外，定位于V1/V2和V3/C4包膜区的序列含有残基，如果去糖基化，可以显著增强病毒与？4？7结合的亲和力。这种高亲和力结合HIV-1被认为是优先通过粘膜途径传播的。我们的实验室最近已经证明，在急性IV和直肠内SIV感染之前和期间注射一种主要的抗？4？7单抗，可以显著降低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。这些研究的目的是：1)通过确定？4？7给药是否能有效地降低阴道内感染、SIV感染后、低重复剂量阴道内感染以模拟自然传播的动物的GALT病毒载量，以及d)单用或联合使用CCR9小分子抑制剂是否能更有效和更持久地控制GALT病毒血症，来确定这些先前发现的临床实用性；2)确定肠道组织的组织病理学分析，重点描述参与维持肠道组织完整性的蛋白质的作用，确定细菌转运的动力学和肠道组织通透性的生理测量；以及3)确定？4？7诱导其作用的机制a)通过确定？4？7单抗是否通过阻断？4？7的受体功能或通过使用与？4？7结合或不结合？4？7的具有复制能力的重组SIV包膜结构来阻断？4？7表达细胞的转运来介导其作用；b)通过使用W.T.&低v/S高亲和力结合？4？7的重组env去糖基化SHV来确定抗？4？7治疗的体内效应是否受包膜糖基化水平的影响，C)使用我们实验室开发的最新优化的实时“实时”PET-CT扫描技术，确定病毒和CD4+细胞在对照组和？4？7组动物中的组织/器官定位。认识到有效的艾滋病毒疫苗不仅需要诱导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，这突显了这些研究的重要性。 与公共卫生相关：HIV/SIV似乎都使用？4？7，这是一种由CD4+T细胞表达的分子，作为替代的共同受体。我们的实验室已经使用了一种抗？4？7分子的单抗，并表明在急性静脉感染之前和期间用单抗治疗猴子可以显著减少胃肠道中的病毒载量。我们建议开展更详细的研究，以确定这些初步发现的临床用途，以确定我们是否可以“钝化”最初的胃肠道病理，这将极大地增强我们对急性感染期间涉及的致病机制的理解。