Mapping the up-regulation of Human Endogenous Retrovirus K with respect to the development of cancer and other diseases

2001年对人类基因组的破译显示，大约8%的基因与病毒基因相似，这表明病毒起源于此。随后对动物基因组的破译表明，病毒入侵和定居基因组已有数百万年的历史。我们称这些存在于我们基因组中的病毒为内源性逆转录病毒（erv）。虽然有许多研究将ERV与动物疾病联系起来，但在人类身上没有明确的联系，尽管最近发现一种古老的ERV与免疫系统癌症霍奇金淋巴瘤有关。我建议研究人类基因组中最近活跃的ERV，即HERV-K HML-2 (HK2)，研究其在人类疾病发展过程中的表达，重点是癌症。为什么把重点放在HK2？我们知道erv与其宿主紧密相连。当病毒感染较温和时，它们在宿主基因组中的定殖效率较好。一个简单的例子说明了这一原则：如果病毒通过感染杀死宿主，那么它也会通过破坏宿主的“殖民地”来自杀。我最近的研究表明，当erv失去在不同细胞和个体之间移动的能力时，它们会更有效地定植基因组。因此，我最近的研究表明，被转化为在细胞生命周期内使用的erv除了对抗病毒反应隐身外，对宿主也更温和、更友好。另一方面，没有通过改变其生命周期来适应的病毒，预计会更具致病性。HK2属于这类具有潜在致病性的erv。我将首先建立一个强大的实验室框架，并描述HK2在大量患者（癌症或艾滋病毒感染）和健康志愿者中的表达强度。这将使我能够研究整个疾病发展过程中HK2表达的历史。最后，我将研究HK2是否由于其上调而在同一患者的细胞之间传播，以确定它是否也可能具有传染性并传播给其他人。该项目将邀请来自牛津大学、哈佛大学、雅典大学和帝国理工学院的研究癌症流行病学、艾滋病毒和其他逆转录病毒的研究人员和免疫学家作为合作者。一个拥有超过10万份自1990年以来深度冷冻和收集的样本的大型生物库将提供所需的800份样本中的大部分。该项目预计将对了解癌症及其发展产生影响，但它也可能被证明对输血和血液制品安全具有高度重要性。

The deciphering of the human genome in 2001 revealed that around 8% resembles viral genes, suggesting a viral origin. Subsequent deciphering of animal genomes has shown that viruses have been invading and colonizing genomes for millions of years. We call these viruses, which reside within our genomes, endogenous retroviruses (ERVs). While there are many studies connecting ERVs with disease in animals, in humans no definitive link has been demonstrated, although recently an ancient ERV was connected with Hodgkins lymphoma, a cancer of the immune system. I propose to study the most recently active ERV within the human genome, namely HERV-K HML-2 (HK2), with respect to its expression during the development of human disease, focusing on cancer. Why focus on HK2? We know that ERVs are strongly connected with their host. Their efficiency in colonizing host genomes is better when the viral infection is milder. A simple example demonstrates this principle: if a virus kills the host by infection then it commits suicide by destroying its "colony" as well. My recent study has shown that ERVs colonize genomes more efficiently when they lose their ability to move between different cells and individuals. Therefore, my recent study suggests that ERVs, which were transformed to use within cell life-cycle apart from being stealth to antiviral responses, they are also milder and more friendly to their host. On the other hand, viruses that have not adapted by changing their life-cycle, are expected to be more pathogenic. HK2 belongs to this kind of potentially pathogenic ERVs.I will firstly develop a robust laboratory framework and describe the intensity of the HK2 expression in a large sample of patients (with cancer or HIV infections) and healthy volunteers. This will allow me to study the history of HK2 expression throughout the development of diseases. Finally, I will study if HK2 is spreading between cells of the same patient as a result of its up-regulation, to determine whether it could also be infectious and transmitted to other people as well.The project will engage as collaborators researchers working on cancer epidemiology, HIV and other retroviruses and immunologists from the Universities of Oxford, Harvard, Athens and Imperial College. A large biobank with more than 100,000 samples deeply frozen and collected since 1990 will contribute the majority of the required 800 samples. The project is expected to have an impact in understanding cancer and its development, but also it could prove to be of high importance for transfusion and blood product safety.