Interaction of HIV envelope with cell surface receptors

HIV 包膜与细胞表面受体的相互作用

• 批准号: 8946348
• 负责人: Anthony S. Fauci
• 金额: $ 61.27万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8946348
• 关键词: Address; Affinity; Binding; CD4 Antigens; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Surface Receptors; Cells; Chemokine (C-C Motif) Receptor 5; Chronic; Development; Disease; Environment; Event; Genetic; Genital system; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Receptors; HIV envelope protein; HIV vaccine; Infection; Infection prevention; Integrin alpha4; Interphase Cell; Lymphoid Tissue; Maintenance; Molecular; Mucous Membrane; Process; Relative (related person); Route; Staging; Structure; Surface; Variant; Viral; Virion; Virus; fitness; interest; prevent; receptor; transmission process

It is well-established that the most frequent route of HIV transmission occurs across mucosal tissues. Unfortunately, the earliest events in mucosal transmission are poorly defined. We regard a comprehensive understanding of these events as critically important information that can be utilized in the development of an effective HIV vaccine. A key feature of mucosal transmission of HIV is that it is typically inefficient. The virus must overcome multiple structural barriers and only achieves productive infection upon gaining access to metabolically active CD4+ T cells. This process requires that the HIV envelope protein first binds to the CD4 receptor and subsequently to a co-receptor (CCR5 or CXCR4). However, the CD4 receptor is expressed at high levels not just on metabolically activated cells, but also on resting cells, which are a poor substrate for productive infection. We have identified the integrin alpha4-beta7 as an additional HIV receptor on the surface of CD4+ T cells. Alpha4beta7 is not an entry receptor, however, unlike CD4, integrin alpha4-beta7 is preferentially expressed on a subset of cells in mucosal tissues that are activated. We are addressing the hypothesis that a direct interaction between gp120 and alpha4-beta7 provides important advantages that facilitate transmission across mucosal surfaces. By engaging alpha4-beta7 on a susceptible cell, a virion is able to target a relevant subset of CD4+ T cells that is relatively more susceptible to infection. In addition, alpha4-beta7+ CD4+ T cells migrate from genital mucosa into gut lymphoid tissues where an optimal cellular environment exists for viral replication. In this way, we hypothesize that the specific affinity of the HIV envelope for alpha4-beta7 provides a plausible explanation for the preferential establishment and/or maintenance of HIV replication in GALT. We continue to pursue the goal of better understanding the specific molecular events surrounding mucosal transmission because we regard this as critical information that will allow us to identify new strategies to prevent HIV transmission

众所周知，HIV最常见的传播途径是通过粘膜组织。不幸的是，粘膜传播的最早期事件定义不清。 我们认为，对这些事件的全面了解是至关重要的信息，可用于开发有效的艾滋病毒疫苗。HIV的粘膜传播的一个关键特征是它通常是低效的。该病毒必须克服多种结构障碍，并且只有在获得代谢活性的CD 4 + T细胞后才能实现生产性感染。这个过程需要HIV包膜蛋白首先与CD 4受体结合，然后与辅助受体（CCR 5或CXCR 4）结合。然而，CD 4受体不仅在代谢活化的细胞上以高水平表达，而且在静止细胞上也以高水平表达，静止细胞是生产性感染的不良底物。我们已经鉴定了整合素α 4-β 7作为CD 4 + T细胞表面上的另外的HIV受体。 α 4 β 7不是进入受体，然而，与CD 4不同，整合素α 4-β 7优先表达在粘膜组织中被激活的细胞亚群上。我们正在解决的假设，gp 120和α 4-β 7之间的直接相互作用提供了重要的优势，促进跨粘膜表面的传输。通过在易感细胞上接合α 4-β 7，病毒体能够靶向相对更易受感染的CD 4 + T细胞的相关亚群。此外，α 4-β 7 + CD 4 + T细胞从生殖器粘膜迁移到肠道淋巴组织中，其中存在用于病毒复制的最佳细胞环境。通过这种方式，我们假设HIV包膜对α 4-β 7的特异性亲和力为GALT中HIV复制的优先建立和/或维持提供了合理的解释。 我们继续追求更好地了解粘膜传播周围的特定分子事件的目标，因为我们认为这是使我们能够确定预防艾滋病毒传播的新策略的关键信息