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

HIV-1的传播主要依赖于受感染的T细胞的迁移。出乎意料的是，一小部分感染者 最近发现T细胞以小的合胞体存在，包含多达四个核。重要的是，这些实体 与有时在病毒晚期可以观察到的较大合胞体不同 传播/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， 在感染的最初阶段就已经存在。我们在生理相关的体外环境中的分析 进一步证明了小T细胞合胞体可以将病毒转移到未感染的细胞，这表明它们可以 有助于早期病毒传播。 通过R 01的应用，我们建议开始探索HIV-1诱导的小合胞体是否真的可以 直接导致病毒传播。我们将通过表征运动/迁移特性开始我们的研究 并分析它们在病毒传播动力学中的作用。宿主和病毒因素参与 还将研究合胞体隔室的稳态维持。重要的是，我们招募了 在一个领先的HIV蛋白质组学实验室的支持下，全面绘制合胞体的表达谱。 从这项工作中得到的数据是否应该支持合胞体对病毒感染有重要作用的假设？ 为了加强传播，我们将寻求更多的资金，以研究针对这些实体的潜在战略。

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.