The Host Response Against HIV-1-induced T Cell Syncytia

宿主针对 HIV-1 诱导的 T 细胞合胞体的反应

基本信息

批准号：
10204991
负责人：
Markus Thali
金额：
$ 19.5万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-24 至 2023-05-31
项目状态：
已结题

项目摘要

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.

HIV-1 的传播很大程度上取决于受感染 T 细胞的迁移。没想到只有一小部分受感染的 T 细胞以小合胞体形式存在，最多包含四个细胞核。重要的是，这些实体是不是较大的巨噬细胞或树突状细胞合胞体的前体，后者可以在晚期观察到病毒传播/发病机制的阶段。相反，如三个独立的活体内所示影像学研究显示，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小 T 细胞合胞体可以传播病毒未感染的细胞，表明它们直接促进病毒传播。通过这个 R21 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。我们假设他们这样做是因为表面表达免疫调节宿主因子与受感染的单核细胞中的免疫调节宿主因子不同。如此改变的表面配置文件将触发不同的、至少部分更强的先天免疫反应，这反过来又可以支持病毒传播，例如，局部炎症可以帮助招募潜在的靶细胞病毒复制的场所。如果这项探索性工作产生的数据支持我们的假设，我们将进一步追求资助以研究宿主对合胞体反应改变的机制基础。