Role of the intercellular heterogeneity, epigenetics and viral factors in the decision between lytic replication and latency of human herpesvirus 6

细胞间异质性、表观遗传学和病毒因素在人疱疹病毒6裂解复制和潜伏期决定中的作用

• 批准号: 470694808
• 负责人: Professor Dr. Benedikt Bertold Kaufer, Ph.D.
• 金额: --
• 依托单位: Institut für Virologie (WE05)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/470694808?language=en
• 关键词: Role; intercellular; heterogeneity; epigenetics; viral

Human herpesvirus 6 (HHV-6) infects almost all humans within the first two years of life, causes Roseola infantum and is linked to a number of severe diseases. Upon primary infection, HHV-6 establishes a persistent infection in the host for life, known as latency. In latently infected cells, the HHV-6 genome can integrate into the telomeres, ensuring the maintenance of the virus genome. Intriguingly, infection of PBMCs and various clonal T-cell lines with HHV-6 can result in either lytic replication or latency. Beyond that, it remains unknown, why some cells of a clonal population support lytic replication, while the virus establishes latency in others. Importantly, individual cells of a clonal cell line differ in their transcriptional state, indicating that these differences in gene expression could influence the lytic/latent decision. In addition, we recently demonstrated that latent HHV-6 genomes are efficiently silenced upon infection using next generation sequencing. This coincided with a condensed chromatin state and repressive chromatin marks, suggesting that epigenetic silencing drives HHV-6 into latency. Therefore, we hypothesize that the transcriptional state of the cell, chromosomal integration of the virus genome, specific viral/cellular factors and/or epigenetic modifications on the virus genome influence the decision between lytic replication and latency. We will address this hypothesis in three specific objectives; (i) we will assess if transcriptional signatures influence the outcome of HHV-6A infection and will examine if selected differentially expressed genes influence the decision between lytic replication and latency, (ii) we will investigate the role of integration and the U94 protein in the establishment of latency using recombinant viruses that lack these factors and (iii) we examine if epigenetic modifications and cellular factors influence the outcome of HHV-6A infection. Our proposed work will shed light on the decision between lytic replication and latency of this ubiquitous human pathogen.

人类疱疹病毒6型（HHV-6）在两岁以内感染几乎所有人，引起婴儿红疹，并与许多严重疾病有关。初次感染后，HHV-6在宿主体内建立终身持续感染，称为潜伏期。在潜伏感染的细胞中，HHV-6基因组可以整合到端粒中，确保病毒基因组的维持。有趣的是，pbmc和各种克隆t细胞系感染HHV-6可导致裂解复制或潜伏期。除此之外，为什么克隆群体中的一些细胞支持裂解复制，而病毒在其他细胞中建立潜伏期，这仍然是未知的。重要的是，克隆细胞系的单个细胞的转录状态不同，表明这些基因表达的差异可能影响裂解/潜伏的决定。此外，我们最近证明潜伏的HHV-6基因组在感染后使用下一代测序有效地沉默。这与浓缩染色质状态和抑制染色质标记相吻合，表明表观遗传沉默使HHV-6进入潜伏期。因此，我们假设细胞的转录状态、病毒基因组的染色体整合、特定的病毒/细胞因子和/或病毒基因组的表观遗传修饰会影响裂解复制和潜伏期之间的决定。我们将通过三个具体目标来解决这一假设；(i)我们将评估转录特征是否会影响HHV-6A感染的结果，并检查所选择的差异表达基因是否会影响裂解复制和潜伏期之间的决定；（ii）我们将研究整合和U94蛋白在使用缺乏这些因素的重组病毒建立潜伏期中的作用；（iii）我们将检查表观遗传修饰和细胞因素是否会影响HHV-6A感染的结果。我们提出的工作将阐明这种普遍存在的人类病原体的裂解复制和潜伏期之间的决定。