Role of HIV Envelope Proteins In Viral Replication and HIV Pathogenesis

该项目包括gp120信号转导通过多个受体在HIV发病机制中的作用。我们最初评估了gp120通过CD4和CCR5信号传导的影响，并将这些研究扩展到通过整合素a4b7信号传导。这些研究的一个关键发现是，HIV包膜通过这些受体发出信号，可以促进病毒复制。这种能力在病毒在肠道组织中的复制中起着特别重要的作用。在感染的早期阶段，当激活的靶细胞有限时，gp120传递的信号可以提供生产性感染所需的刺激。我们在HIV/SIV感染的非人灵长类动物（NHP）模型中验证了这一假设，并确定阻断gp120与a4b7相互作用的抗体可以阻止恒河猴粘膜传播模型中的传播。在我们目前的工作中，我们正在探索gp120 V2诱导CD4+ T细胞分化的方式。我们也在探索V2共刺激在持续HIV储存库形成中的作用。

This project encompasses the role of gp120 signal transduction through multiple receptors in HIV pathogenesis. We initially evaluated the impact of gp120 signaling through CD4 and CCR5, and have expanded these studies to include signaling through integrin a4b7. A key finding of these studies is that the HIV envelope, by signaling through these receptors, can promote viral replication. This capacity can play a particularly important in viral replication in gut tissues. In the earliest stages of infection, when activated target cells are limited, signals delivered by gp120 can provide the stimulus required for productive infection. We tested this hypothesis in a non-human primate (NHP) model of HIV/SIV infection and determined that an antibody that blocks gp120 interactions with a4b7 prevents transmission in a rhesus macaque model of mucosal transmission. In our current work we are exploring the way in which gp120 V2 induces the differentiation of CD4+ T cells. We are also exploring the role of V2 costimulation in the formation of persistent HIV reservoirs.