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（由申请人提供）：在性传播时，HIV 必须感染生殖器或肛门粘膜内足够数量的易感靶细胞，才能建立全身感染。这一过程的细节很难确定，特别是在感染中。人类，但可能包含改善艾滋病毒生物医学预防的关键在这项研究中，我们的目的是更好地描述宿主体内可能影响艾滋病毒传播时艾滋病毒感染易感性的生物决定因素，目的是制定策略。 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 HIV 获得和疾病进展中的作用。 HIV 在感染后的最初几周内迅速定位于肠道组织，并且在整个感染过程中肠道内的 CD4+ T 细胞也经历了最严重的消耗。此外，α4β7 通过 HIV 结合并发出信号。 gp120 分子以模仿其天然受体 MAdCAM-1 的方式，这种 α4β7 结合在最近传播的/创始人 HIV gp120 分子中更加明显，进一步表明我们已经表征了 α4β7 在宫颈 CD4+ T 细胞上的作用并发现。 CD69、CCR5 和 Th17 细胞优先表达 我们还通过多种测定表明 HIV 优先在 α4β7+ CD4+ T 细胞中复制，并且α4β7 表达与 CD4 和 CCR5 紧密相关，这些抗体针对 α4β7 与 HIV gp120 结合的位点，这是 RV144 疫苗试验中保护作用的主要相关性；强筛效应的证据进一步支持了这一点。最近，在非人类灵长类动物模型中，我们发现施用靶向重组的α4β7。感染前的恒河猴单克隆抗体可以保护动物免受 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，即高度激活且具有潜在感染能力的细胞。 基于这一假设，我们将测试血液和生殖器粘膜中α4β7和/或其配体水平的增加是否与HIV感染水平的增加有关。该提案利用了 CAPRISA004 和 008 生物样本库，它提供了确定这些标记物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，如果这些数据被证明是正确的，则意味着这些数据是正确的。 α4β7 在 HIV 与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，其阻断作用已在炎症性肠病领域进行了测试，可能代表一种具有 HIV 预防潜力的产品，可以在体内进一步验证这一概念。对以宿主为导向的艾滋病毒预防策略具有重要意义。