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，最常见的HIV传播途径是跨粘膜组织。不幸的是，粘膜传播中最早的事件的定义很差。 我们将对这些事件的全面理解视为非常重要的信息，可用于开发有效的HIV疫苗。 HIV的粘膜传播的一个关键特征是它通常效率低下。该病毒必须克服多个结构性屏障，并且仅在获得代谢活性CD4+ T细胞后才能实现生产性感染。此过程要求HIV包膜蛋白首先与CD4受体结合，然后与共受体（CCR5或CXCR4）结合。但是，CD4受体不仅在代谢活化的细胞上，而且在静息细胞上以高水平表达，这是生产感染的较差的底物。我们已经将整联蛋白alpha4-Beta7鉴定为CD4+ T细胞表面上的附加HIV受体。 但是，与CD4不同，alpha4beta7不是进入受体，整合素alpha4-beta7优先在被激活的粘膜组织中的细胞子集中表达。我们正在解决以下假设：GP120和Alpha4-Beta7之间的直接相互作用提供了促进跨粘膜表面传播的重要优势。通过在易感细胞上吸引alpha4-beta7，病毒体能够靶向相关的CD4+ T细胞子集，CD4+ T细胞相对容易感染。此外，α4-Beta7+ CD4+ T细胞从生殖器粘膜迁移到肠道淋巴组织中，其中存在最佳的细胞环境以进行病毒复制。通过这种方式，我们假设HIV信封对Alpha4-Beta7的特定亲和力为Galt中HIV复制的优先建立和/或维持的优先建立和/或维持提供了合理的解释。 我们继续追求更好地理解围绕粘膜传播的特定分子事件的目标，因为我们将其视为关键信息，这将使我们能够确定防止艾滋病毒传播的新策略