Integrin a4b7 as a predictor of HIV acquisition and pathogenesis

整合素 a4b7 作为 HIV 获得和发病机制的预测因子

• 批准号: 8838886
• 负责人: Aftab A. Ansari
• 金额: $ 16.16万
• 依托单位: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838886
• 关键词: AIDS prevention; Address; Animal Model; Animals; Antibodies; Anus; Area; Bacterial Translocation; Binding; Biological; Biological Assay; Blocking Antibodies; Blood; CCR5 gene; CD14 gene; CD4 Positive T Lymphocytes; Cells; Cervical; Clinical; Clinical Trials; Cohort Studies; Communicable Diseases; Data; Deltastab; Dendritic Cells; Detection; Disease Progression; Dose; Enhancers; Epitopes; Event; FDA approved; Frequencies; Genital system; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; High Risk Woman; Homing; Human; Immune; Immune system; Immunologic Markers; In Vitro; Infection; Inflammatory Bowel Diseases; Integrins; Investigation; Lead; Ligands; Link; Macaca mulatta; Measures; Modality; Modeling; Monoclonal Antibodies; Mucous Membrane; Outcome; Pathogenesis; Pathway interactions; Plasma; Play; Predisposition; Prevention strategy; Process; Prospective Studies; Publishing; Recombinants; Research; Research Design; Role; Route; Safety; Sampling; Signal Transduction; Site; Specimen; Systemic infection; T-Lymphocyte Subsets; Testing; Time; Tissues; Vagina; Viral; Viral Load result; Virus; Work; base; biobank; cohort; density; disorder prevention; experience; follow-up; high risk; improved; in vivo; microbial; mucosal addressin cell adhesion molecule-1; nonhuman primate; pandemic disease; prevent; prospective; public health relevance; receptor; sexual HIV transmission; stem; tool; transmission process; vaccine trial

 DESCRIPTION (provided by applicant): At the time of sexual transmission, HIV must infect a sufficient number of susceptible target cells within the genital or anal mucosa in order to establish systemic infection. The details of this process have been difficult to ascertain, particularly in humans, but may contain the key to improving biomedical HIV prevention. In this study we aim to better characterize the biological determinants in the host that might influence susceptibility to HIV infection at the time of HIV transmission, with a goal of deriving a strategy that can block HIV infection at the mucosal level. In particular, we will focus our efforts on understanding the role of the gut homing integrin α4β7 and its ligands in HIV acquisition and disease progression. This is in part because regardless of the route of infection, HIV rapidly localizes to gut tissues within the first few weeks post-infection, and the gut also experiences the most severe depletion of CD4+ T cells throughout the course of infection. Moreover, α4β7 binds and signals through HIV gp120 molecules in a way that mimics its natural receptor, MAdCAM-1. This α4β7-binding is even more pronounced in recently transmitted/founder HIV gp120 molecules, further suggesting a role for transmission. We have characterized α4β7 on cervical CD4+ T cells and found preferential expression with CD69, CCR5, and Th17 cells. We have also shown by multiple assays that HIV preferentially replicates in α4β7+ CD4+ T cells, and α4β7 expression is tightly linked to both CD4 and CCR5. HIV-specific antibodies that are directed to the site where α4β7 binds to HIV gp120 were the main correlate of protection in the RV144 vaccine trial; this was further supported by evidence for a strong sieve effect at a key residue in the α4β7-gp120 binding epitope. More recently, in the non-human primate model, we showed that the administration of an α4β7 targeting recombinant rhesus monoclonal antibody prior to infection protected animals from highly pathogenic low dose vaginal challenge with SIVmac251. Taken together, these data suggest that α4β7 may help the virus identify ideal target cells in the genital mucosa, i.e. cells that are both highly activated and have potential to migrate to the gut tissue, an area rich in HIV target cells. Based on this hypothesis, in the current proposal we will test whether increased levels of α4β7 and/or its ligands in the blood an genital mucosa are associated with increased levels of HIV acquisition and disease progression. This proposal makes use of the CAPRISA004 and 008 biorepository, which provides the statistical power and prospective study design required to determine the relevance of these markers in a real-world setting. If proven correct these data would imply that α4β7 plays an important role in the early interaction between HIV and host mucosal immune system, and that its blockade, which is already extensively tested in the inflammatory bowel disease field, could represent a product with HIV prevention potential. Further verification of this concept in vivo could have important implications for host-directed HIV prevention strategies.

 描述(申请人提供)：在性传播时，艾滋病毒必须感染生殖器或肛门粘膜内足够数量的易感目标细胞，才能确定系统性感染。这一过程的细节很难确定，特别是在人类身上，但可能包含改善生物医学艾滋病毒预防的关键。在这项研究中，我们的目标是更好地表征宿主中可能影响艾滋病毒传播时对艾滋病毒感染易感性的生物决定因素，目的是制定一种策略 这可以在粘膜层面阻止艾滋病毒感染。特别是，我们将集中精力了解肠道归巢整合素α4β7及其配体在艾滋病毒感染和疾病进展中的作用。这在一定程度上是因为，无论感染途径如何，艾滋病毒在感染后的头几周内迅速定位于肠道组织，肠道在整个感染过程中也经历了最严重的CD4+T细胞耗尽。此外，α4β7通过HIV gp120分子结合并发出信号，其方式与其天然受体MadCAM-1类似。这种α4β7结合在最近传播的/创建者HIV gp120分子中更加明显，进一步表明了传播的作用。我们鉴定了α4β7在宫颈CD 4+T细胞上的表达，并发现CD6 9、CCR5和Th17细胞具有优势表达。我们还通过多项检测表明，艾滋病毒优先在α4β7+CD 4+T细胞中复制，并且α4 CCR7的表达与CD 4和β5密切相关。针对α4β7与HIV gp120结合部位的艾滋病毒特异性抗体是RV144疫苗试验中保护作用的主要相关因素；有证据表明，α4β7-gp120结合表位的关键残基具有很强的筛选效应，进一步支持了这一点。最近，在非人类灵长类动物模型中，我们表明，在感染前给予针对重组猕猴单抗的α4β7可以保护动物免受SIVmac251的高致病性低剂量阴道攻击。综上所述，这些数据表明，α4β7可能有助于病毒识别生殖器粘膜中的理想靶细胞，即既高度激活又有可能 迁移到肠道组织，这是一个富含艾滋病毒靶细胞的区域。基于这一假设，在目前的方案中，我们将测试血液和生殖器粘膜中α4、β7和/或其配体水平的增加是否与艾滋病毒感染和疾病进展的水平增加有关。这一建议利用了CAPRISA004和008生物信息库，它提供了确定这些标记在现实世界环境中的相关性所需的统计能力和前瞻性研究设计。如果这些数据被证实是正确的，将意味着α4β7在艾滋病毒和宿主粘膜免疫系统之间的早期相互作用中发挥着重要作用，并且它的阻断已经在炎症性肠病领域得到了广泛的测试，可能代表着一种具有预防艾滋病毒潜力的产品。在体内进一步验证这一概念可能会对宿主导向的艾滋病毒预防战略产生重要影响。