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， 最近发现，受感染的T细胞以小的合胞体存在，含有多达四个核。重要的是， 这些实体不同于较大的合胞体，合胞体有时可以在病毒的晚期观察到。 传播/发病机制。事实上，正如三项独立的活体成像研究所示， 在感染的最初阶段就已经存在了。我们的分析在生理相关的体外 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 它们可以促进病毒的早期传播。 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可以 实际上直接促进了病毒传播。我们将从描述 合胞体的运动/迁移特性，并分析它们在病毒传播动力学中的作用。主机 还将研究与合胞体区室的稳态维持有关的病毒因子。 重要的是，我们已经招募了领先的艾滋病毒蛋白质组学实验室的支持，以全面 绘制合胞体的表达谱。 这项工作的数据是否应该支持合胞体对 病毒传播，我们将寻求进一步的资金，以研究潜在的战略，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.