Mechanisms of cell motility inhibition by the HIV-1 pathogenesis factor NEF

HIV-1致病因子NEF抑制细胞运动的机制

• 批准号: 180582868
• 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: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/180582868?language=en
• 关键词: Mechanisms; cell; motility; inhibition; HIV

The NEF protein is a virally encoded pathogenesis factor of Human Immunodeficiency Viruses (HIV) that promotes virus replication and immune evasion of virus producing cells in the infected host. We previously identified inhibition of host cell motility as a highly conserved biological property of NEF and established inhibition of actin remodeling as a molecular mechanism that is necessary but not sufficient for this activity. The aim of this proposal is to define the actin-independent activities NEF employs to modulate cell motility. This will be achieved by combining in vivo analyses of NEF- expressing zebrafish primordial germ cells (PGC) with ex vivo studies of virally infected primary human T lymphocytes and macrophages. Advanced real time imaging approaches will provide detailed characterization of the defects induced by NEF on a single cell level and will be directly coupled to quantification of cell motility. Concomitant genetic and biochemical analyses are designed to unravel the underlying molecular mechanisms. Together these interdisciplinary studies will employ NEF as a valuable tool to decipher basic principles of PGC migration and are expected to yield important insights into the mechanism and patho-physiological impact on host cell motility.

NEF蛋白是人类免疫缺陷病毒(HIV)的一种病毒编码的致病因子，它促进病毒复制和感染宿主中产生病毒的细胞的免疫逃避。我们以前发现抑制宿主细胞的运动是NEF的一种高度保守的生物学特性，并将抑制肌动蛋白重塑作为这一活性的必要但不充分的分子机制。这项建议的目的是定义NEF用来调节细胞运动的肌动蛋白非依赖性活动。这将通过体内对表达NEF的斑马鱼原始生殖细胞(PGC)的分析与对病毒感染的原始人类T淋巴细胞和巨噬细胞的体外研究相结合来实现。先进的实时成像方法将在单个细胞水平上提供对NEF引起的缺陷的详细表征，并将直接与细胞运动性的量化相结合。伴随而来的遗传和生化分析旨在揭示潜在的分子机制。总之，这些跨学科的研究将使用NEF作为一个有价值的工具来破译PGC迁移的基本原理，并有望对宿主细胞运动的机制和病理生理影响产生重要的见解。

项目成果

HIV-1 reprograms the migration of macrophages.

• DOI: 10.1182/blood-2014-08-596775
• 发表时间: 2015-03
• 期刊: Blood
• 影响因子: 20.3
• 作者: C. Vérollet;Shanti Souriant;Emilie M. Bonnaud;P. Jolicoeur;B. Raynaud-Messina;Cassandre Kinnaer;I. Fourquaux;Andrea Imle;S. Bénichou;O. Fackler;Renaud Poincloux;I. Maridonneau-Parini

D186/D190 is an allele-dependent determinant of HIV-1 Nef function.

D186/D190 是 HIV-1 Nef 功能的等位基因依赖性决定因素

• DOI: 10.1016/j.virol.2016.08.012
• 发表时间: 2016
• 期刊: Virology
• 影响因子: 3.7
• 作者: Böhmer;Fackler O.T.
• 通讯作者: Fackler O.T.

HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface

• DOI: 10.4049/jimmunol.1701420
• 发表时间: 2018-11-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Lamas-Murua, Miguel;Stolp, Bettina;Fackler, Oliver T.
• 通讯作者: Fackler, Oliver T.

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

HIV-1 Nef 通过体内有限环境干扰 T 淋巴细胞循环

• DOI: 10.1073/pnas.1204322109
• 发表时间: 2012
• 期刊: Proceedings of the National Academy of Sciences
• 作者: Coelho;Mendiz;Fackler
• 通讯作者: Fackler

Association with PAK2 Enables Functional Interactions of Lentiviral Nef Proteins with the Exocyst Complex

• DOI: 10.1128/mbio.01309-15
• 发表时间: 2015-09-01
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Imle, Andrea;Abraham, Libin;Fackler, Oliver T.
• 通讯作者: Fackler, Oliver T.