Multiscale analysis of HIV-1-induced small T cell syncytia

HIV-1的传播在很大程度上依赖于受感染T细胞的迁移。出乎意料的是，一小部分 最近发现，受感染的T细胞以小的合胞体形式存在，含有多达四个核。重要的是 这些实体不同于更大的合胞体，后者有时可以在病毒的晚期观察到。 播散/发病机制。事实上，正如三项独立的活体成像研究所显示的那样，他们 已经出现在感染的最早阶段。我们在体外生理学上的分析 设置进一步证明，小T细胞合胞体可以将病毒传播到未感染的细胞，这表明 他们可以为早期病毒传播做出贡献。 有了这个R01应用，我们建议开始探索HIV-1诱导的小合胞体是否可以 确实直接导致了病毒的传播。我们将从以下特征开始我们的调查 合胞体的运动/迁移特性及其在病毒传播动力学中的作用寄主 此外，还将研究与合胞体维持内环境平衡有关的病毒因子。 重要的是，我们已经招募了一家领先的艾滋病毒蛋白质组实验室的支持，以便全面 绘制合胞体的表达图谱。 如果这项工作产生的数据支持合胞体对 病毒传播，我们将寻求进一步的资金，以研究可能的战略，以应对这些 实体。

HIV-1 dissemination critically depends on migration of infected T cells. Unexpectedly, a fraction of the infected T cells was recently found to exist as small syncytia, containing up to four nuclei. Importantly, these entities differ from larger syncytia which sometimes can be observed in late stages of virus dissemination/pathogenesis. Indeed, and as shown in three independent intravital imaging studies, they are present already at the earliest stages of infection. Our analyses in physiologically relevant in vitro settings further documented that small T cell syncytia can transfer virus to uninfected cells, suggesting that they can contribute to early virus dissemination. With this R01 application, we propose to start exploring whether HIV-1-induced small syncytia can indeed directly contribute to virus spread. We will start our investigations by characterizing motility/migration properties of syncytia and analyzing their role in virus transmission dynamics. Host and viral factors involved in homeostatic maintenance of the syncytial compartment will also be studied. Importantly, we have recruited the support of a leading HIV proteomics lab in order to comprehensively map the expression profiles of syncytia. Should the data resulting from this work support the hypothesis that syncytia contribute significantly to virus dissemination, we will pursue further funding in order to study potential strategies against these entities.