Interaction of HIV envelope with cell surface receptors

众所周知，最常见的HIV传播途径发生在粘膜组织之间。不幸的是，粘膜传播的最早事件定义不清。我们认为，全面了解这些事件是极为重要的信息，可用于研制有效的艾滋病毒疫苗。艾滋病毒粘膜传播的一个关键特征是它通常是低效的。病毒必须克服多重结构障碍，只有在进入代谢活跃的CD4+ T细胞后才能实现生产性感染。这一过程要求HIV包膜蛋白首先与CD4受体结合，然后与一个共受体（CCR5或CXCR4）结合。然而，CD4受体不仅在代谢激活的细胞上高水平表达，而且在静止细胞上也表达，静止细胞是生产性感染的不良底物。我们已经确定了整合素alpha4-beta7是CD4+ T细胞表面的另一个HIV受体。然而，与CD4不同的是，整合素alpha4-beta7在被激活的粘膜组织中的一部分细胞上优先表达。我们正在解决gp120和alpha4-beta7之间的直接相互作用提供了促进粘膜表面传播的重要优势的假设。通过在易感细胞上加入alpha4-beta7，病毒粒子能够靶向相对更容易感染的CD4+ T细胞的相关亚群。此外，alpha4-beta7+ CD4+ T细胞从生殖器粘膜迁移到肠道淋巴组织，肠道淋巴组织为病毒复制提供了最佳的细胞环境。通过这种方式，我们假设HIV包膜对alpha4-beta7的特异性亲和力为在GALT中优先建立和/或维持HIV复制提供了合理的解释。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，因为我们认为这是关键信息，将使我们能够确定预防艾滋病毒传播的新策略

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