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: 8555852
• 负责人: Anthony S. Fauci
• 金额: $ 46.94万
• 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/8555852
• 关键词: Affinity; CCR5 gene; CD4 Antigens; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Surface Receptors; Cells; Development; Disease; Environment; Event; Exhibits; Genetic; Genetic Variation; 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; Investigation; Lymphoid Tissue; Maintenance; Molecular; Mucous Membrane; Patients; Process; Protein Binding; Staging; Surface; Variant; Viral; Virion; Virus; prevent; receptor; transmission process

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.

了解HIV粘膜传播的特定分子事件将有望提供可用于开发有效HIV疫苗的关键信息。几条研究线显示HIV通过粘膜表面的传播是无效的。病毒必须克服多重结构障碍，并最终感染代谢活性的CD 4 + T细胞。感染过程需要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。与CD 4受体不同，整合素α 4-β 7在粘膜组织中倾向于被代谢活化的细胞亚群上表达。我们假设HIV gp 120和α 4-β 7之间的直接相互作用为HIV提供了两个优势，使其能够以更有效的方式通过粘膜表面传播。通过在易感细胞上接合α 4-β 7，病毒体能够靶向对感染高度易感的重要的CD 4 + T细胞亚群。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。以这种方式，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机制解释。了解粘膜传播周围的特定分子事件将有望使我们能够确定预防HIV传播的新策略。