Die Infektion endothelialer Zellen mit dem humanen Herpesvirus 8 (KSHV/HHV8): Mechanismen der Persistenz, Replikation und abnormaler Differenzierung

人疱疹病毒 8 (KSHV/HHV8) 感染内皮细胞：持续、复制和异常分化的机制

• 批准号: 5388696
• 负责人: Professor Dr. Thomas Schulz
• 金额: --
• 依托单位: Institut für Virologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2002
• 资助国家: 德国
• 起止时间: 2001-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5388696?language=en
• 关键词: Die; Infektion; endothelialer; Zellen; mit

Kaposi's Sarcoma associated herpesvirus (KSHV/HHV-8), is an essential factor in the pathogenesis of Kaposi's sarcoma (KS), a tumour derived from endothelial cells. KSHV infects, and probably persists in, endothelial cells and induces their atypical differentiation into KS spindle cells, the hallmark of this tumour. Viral proteins expressed during latent persistence and lytic replication may contribute to the development KS spindle cells. However, in characterising the function of individual viral proteins, all previous studies have studied them in isolation, outside the context of the remainder of the virus genome, and mostly after overexpression. The experience with other herpesviruses suggests that this may lead to misleading interpretations. The lack of an efficient in vitro culture system has so far precluded experiments with KSHV mutants. Given the recent improvements in cell culture systems for KSHV we propose to construct a recombinant molecular clone of KSHV in a 'bacterial artificial chromosome' (BAC) and to use it for the generation of a mutant transposon library as well as mutants of individually targeted genes. The aim of the proposal is to identify KSHV mutants that have lost the ability to replicate and/or persist in endothelial cells and to induce spindle cell formation in primary endothelial cells. This will allow the identification of viral genes that are essential for KSHV-mediated pathogenesis in endothelial cells. The results will contribute to our understanding of how herpesviruses in general infect and persist in endothelial cells.

卡波西肉瘤相关疱疹病毒（KSHV/HHV-8）是卡波西肉瘤（KS）发病机制中的重要因素，KS是一种来源于内皮细胞的肿瘤。KSHV感染并可能持续存在于内皮细胞中，并诱导其非典型分化为KS梭形细胞，这是该肿瘤的标志。病毒在潜伏期和裂解性复制过程中表达的蛋白质可能有助于KS梭形细胞的发育。然而，在表征单个病毒蛋白质的功能时，所有先前的研究都是在病毒基因组的其余部分的背景之外孤立地研究它们，并且大多是在过表达之后。其他疱疹病毒的经验表明，这可能导致误解。由于缺乏有效的体外培养系统，迄今为止还无法进行KSHV突变体的实验。鉴于KSHV细胞培养系统的最新进展，我们建议在“细菌人工染色体”（BAC）中构建KSHV的重组分子克隆，并将其用于产生突变转座子文库以及单独靶向基因的突变体。该提案的目的是鉴定失去在内皮细胞中复制和/或持续存在能力并诱导原代内皮细胞中梭形细胞形成的KSHV突变体。这将允许识别的病毒基因是必不可少的KSHV介导的发病机制在内皮细胞。这些结果将有助于我们理解疱疹病毒一般如何感染和持续存在于内皮细胞中。