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（由适用提供）：在性传播时，HIV必须在生殖器或肛门粘膜中感染足够数量的易感靶细胞，以建立全身感染。这个过程的细节很难确定，特别是在人类中，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，我们旨在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的易感性的生物决策者，目的是推导策略 这可以阻止粘膜水平的艾滋病毒感染。特别是，我们将重点放在理解肠道归巢整合素α4β7及其配体在HIV获取和疾病进展中的作用。这部分是因为不管感染的途径如何，HIV在感染后的头几周内迅速定位于肠道组织，并且在整个感染过程中，肠道也经历了CD4+ T细胞最严重的耗竭。此外，α4β7通过模仿其自然受体MadCAM-1的方式通过HIV GP120分子结合和信号。在最近传输/创始人的HIV GP120分子中，这种α4β7结合更加明显，进一步表明了传播的作用。我们已经在宫颈CD4+ T细胞上表征了α4β7，并发现了CD69，CCR5和TH17细胞的优先表达。我们还通过多种测定表明，HIV在α4β7+ CD4+ T细胞中优先复制，并且α4β7表达与CD4和CCR5紧密相关。针对α4β7与HIV GP120结合的部位的HIV特异性抗体是RV144疫苗试验中保护的主要相关性。这进一步得到了证据表明，在α4β7-GP120结合表位中的关键居住下具有强筛效应的证据。最近，在非人类私有模型中，我们表明，靶向重组单克隆抗体的α4β7在感染动物之前受到SIVMAC251的高度致病性低剂量阴道挑战。综上所述，这些数据表明α4β7可以帮助病毒识别生殖器粘膜中理想的靶细胞，即高度活化并且具有潜力的细胞 迁移到肠道组织，这是一个富含HIV靶细胞的区域。基于这一假设，在当前的提案中，我们将测试血液中α4β7和/或其配体水平的升高是否与生殖器粘膜相关的HIV获取和疾病进展水平增加。该提案利用了Caprisa004和008 Biorepositor，该研究提供了确定这些标记在现实世界中的相关性所需的统计能力和前瞻性研究设计。如果证明是正确的，这些数据将暗示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起重要作用，并且它的阻断已经在炎症性肠道疾病领域进行了广泛测试，可以代表具有HIV预防潜力的产物。进一步验证该概念在体内可能对宿主指导的艾滋病毒预防策略具有重要意义。