Interaction of HIV envelope with cell surface receptors

了解围绕艾滋病毒粘膜传播的特定分子事件有望提供关键信息，可用于开发有效的艾滋病毒疫苗。多项研究表明，艾滋病毒在粘膜表面的传播效率很低。该病毒必须克服多种结构障碍，最终感染具有代谢活性的CD4+T细胞。感染过程要求HIV包膜蛋白首先与CD4受体结合，然后与辅助受体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，而且在静息细胞上也高水平表达，而静息细胞是生产性感染的不良底物。我们发现整合素α4-β7是CD4+T细胞表面的一种额外的HIV受体。与CD4受体不同，整合素α4-β7在粘膜组织中易于代谢激活的细胞亚群上表达。我们假设，HIV gp120和alpha4-beta7之间的直接相互作用为HIV提供了两个优点，使其能够以更有效的方式通过粘膜表面传播。通过与敏感细胞上的α4-β7结合，病毒粒子能够靶向对感染高度敏感的一组重要的CD4+T细胞。此外，Alpha4-Beta7+CD4+T细胞从生殖器粘膜迁移到肠道淋巴组织，在那里存在着病毒复制的最佳细胞环境。这样，HIV包膜与Alpha4-Beta7的特异性亲和力为在GalT中优先建立和/或维持HIV复制提供了一个可信的机械解释。了解围绕粘膜传播的特定分子事件将有望使我们确定防止艾滋病毒传播的新策略。

Understanding the specific molecular events surrounding mucosal transmission of HIV will hopefully provide critical information that can be utilized in the development of an effective HIV vaccine. Several lines of investigation reveal thattransmission of HIV across mucosal surfaces is inefficient. The virus must overcome multiple structural barriers and ultimately infect metabolically active CD4+ T cells. The process of infection requires that the HIV envelope protein binds first to the CD4 receptor and subsequently to a co-receptor, either 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. Unlike the CD4 receptor, integrin alpha4-beta7 is expressed on a subset of cells in mucosal tissues that tend to be metabolically activated. We hypothesize that the direct interaction between HIV gp120 and alpha4-beta7 provides two advantages to HIV that allow it to transmit across mucosal surfaces in a more efficient manner. By engaging alpha4-beta7 on a susceptible cell, a virion is able to target an important subset of CD4+ T cells that is highly 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, the specific affinity of the HIV envelope for alpha4-beta7 provides a plausible mechanistic explanation for the preferential establishment and/or maintenance of HIV replication in GALT. Understanding the specific molecular events surrounding mucosal transmission will hopefully allow us to identify new strategies to prevent HIV transmission.