Antagonism of Host Cell Restriction and Sensing by HIV-1 Nef

HIV-1 Nef 对宿主细胞限制和感应的拮抗作用

• 批准号: 318144338
• 负责人: Professor Dr. Oliver T. Fackler, Ph.D.
• 金额: --
• 依托单位: Sektion Integrative Virologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/318144338?language=en
• 关键词: Antagonism; Host; Cell; Restriction; Sensing

The goal of this proposal is to dissect the molecular mechanisms behind the restriction to HIV-1 virion infectivity by Serinc5 (S5) and the Nef-mediated antagonism thereof. Our results obtained during the first funding period revealed antagonism of virion-associated S5 as novel principle of Nef antagonism, defined a S5 antagonism motif (S5AM) in the N-terminus of Nef as novel determinant of Nef antagonism, and ruled out that S5 exerts its antiviral activity by altering lipid composition and organisation of HIV particles. In addition, we found that S5 sensitizes HIV-1 particles to enhanced innate immune recognition by monocyte-derived macrophages (MDMs) but not CD4 T lymphocytes. In the second funding period we will build on these results and the collaborative network of the SPP to (i) unravel how Nef antagonises the S5 restriction to HIV-1 particle infectivity with emphasis on the molecular mechanism of action of the S5AM and (ii) dissect mechanism and relevance of S5-mediated induction of innate immune recognition of HIV-1 particles by MDMs. Together, these investigations will yield a comprehensive understanding of the complex interplay between SERINC proteins and viral antagonists in retrovirus replication and pathogenesis.

该建议的目的是剖析Serinc 5（S5）限制HIV-1病毒体感染性的分子机制及其Nef介导的拮抗作用。我们在第一个资助期间获得的结果显示，病毒体相关的S5的拮抗作用是Nef拮抗作用的新原理，将Nef N端的S5拮抗基序（S5 AM）定义为Nef拮抗作用的新决定因素，并排除了S5通过改变HIV颗粒的脂质组成和组织来发挥其抗病毒活性。此外，我们发现S5使HIV-1颗粒对单核细胞衍生的巨噬细胞（MDM）而不是CD 4 T淋巴细胞的增强的先天免疫识别敏感。在第二个资助期内，我们将在这些结果和SPP合作网络的基础上，（i）阐明Nef如何拮抗S5对HIV-1颗粒感染性的限制，重点是S5 AM的分子作用机制，（ii）剖析S5介导的MDM诱导HIV-1颗粒先天免疫识别的机制和相关性。总之，这些调查将产生一个全面的了解SERINC蛋白和逆转录病毒复制和发病机制中的病毒拮抗剂之间的复杂的相互作用。