The Host Response Against HIV-1-induced 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， 受感染的T细胞以包含多达四个核的小合胞体存在。重要的是，这些实体 而不是更大的巨噬细胞或树突状细胞为基础的合胞体的前体，这可以在晚期 病毒传播/发病阶段。相反，如三个独立的活体内 影像学研究表明，它们在感染的最早阶段就已经存在。我们的分析在 生理相关的体外环境进一步证明了小T细胞合胞体可以转移病毒， 未感染的细胞，这表明它们直接有助于病毒传播。 随着R21的应用，我们建议开始探索HIV-1诱导的小合胞体是否也可以 间接促进病毒传播。我们假设它们这样做是因为 免疫调节宿主因子与感染的单核细胞中的免疫调节宿主因子不同。如此改变的表面 概况会引发不同的、至少部分更强的先天免疫反应，而这反过来又可能 支持病毒传播，例如，局部炎症可以帮助募集潜在靶细胞， 病毒复制的场所。 如果从这项探索性工作中得到的数据支持我们的假设，我们将进一步研究。 为了研究宿主对合胞体反应改变的机制基础，

HIV-1 dissemination critically depends on migration of infected T cells. Unexpectedly, a minor fraction of the infected T cells exist as small syncytia, containing up to four nuclei. Importantly, these entities are not precursors for larger, macrophage- or dendritic cell-based syncytia which can be observed in late stages of virus dissemination/pathogenesis. Rather, 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 directly contribute to virus dissemination. With this R21 application, we propose to start exploring whether HIV-1-induced small syncytia can also indirectly contribute to virus spread. We hypothesize that they do that because the surface expression of immunoregulatory host factors differs from that in infected mononucleated cells. Such an altered surface profile would trigger different, at least partially stronger innate immune responses and this, in turn, could support virus spread as, for example, localized inflammation can aid in recruiting potential target cells to sites of virus replication. Should the data resulting from this exploratory work support our hypothesis, we will pursue further funding in order to study the mechanistic basis for the altered host response against syncytia.