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

• 批准号: 10082997
• 负责人: Markus Thali
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-24 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10082997
• 关键词: AIDS/HIV problem; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Nucleus; Cell surface; Cells; Data; Dendritic Cells; Detection; Funding; Giant Cells; HIV; HIV-1; Immune; Immune response; In Situ; In Vitro; Individual; Infection; Inflammation; Innate Immune Response; Innate Immune System; Integration Host Factors; Intervention; Investigation; Ligands; Methods; Minor; Natural Killer Cells; Pathogenesis; Physiological; Play; Positioning Attribute; Proteins; Public Health; Sentinel; Site; Surface; Systemic infection; T-Cell Depletion; T-Lymphocyte; Testing; Viral; Virus; Virus Diseases; Virus Replication; Work; base; cell killing; imaging study; immune activation; immunoregulation; intravital imaging; macrophage; migration; novel; prevent; recruit; response

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传播严重取决于感染T细胞的迁移。出乎意料的是，一小部分 被感染的T细胞以小合胞体的形式存在，最多包含四个核。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菌的前体，可以在最近观察到 病毒传播/发病机理的阶段。相反，如三个独立的插入性 成像研究，它们已经存在于感染的最早阶段。我们的分析 生理上相关的体外环境进一步证明了小型T细胞合成症可以转移病毒 对未感染的细胞，表明它们直接有助于病毒传播。 使用此R21应用程序，我们建议开始探索HIV-1诱导的小型合成体是否也可以 间接促进病毒扩散。我们假设他们这样做是因为 免疫调节宿主因子与感染的单核细胞中的因素不同。这样改变的表面 轮廓会触发不同的，至少部分强大的先天免疫反应，这反过来又可以 支持病毒扩散，例如，局部炎症可以帮助招募潜在的靶细胞 病毒复制的部位。 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 资金以研究改变宿主反应的机械基础。