细胞表观遗传修饰发生在病毒感染过程中。我们先前记录了人类肝癌Huh-7.5细胞的丙型肝炎病毒(HCV)感染导致核心蛋白介导的Aurora激酶B(AURKB)活性降低和组蛋白H3(H3Ser10ph)水平的丝氨酸10磷酸化,影响炎症途径。HCV适应性在感染衍生的细胞表观遗传修饰中的可能作用尚不清楚。
在这里,我们使用HCV种群来解决这个问题,这些HCV种群在一般适应性(传染性后代生产)方面表现出2.3倍的增加,细胞内病毒生长速率的指数期增加了45倍,相对于父母HCV人群。
我们表明感染导致HCV健康依赖,H3Ser10ph水平的平均下降,AURKB,和组蛋白H4在受感染细胞群中的赖氨酸20(H4K20m3)三甲基化。值得注意的是,H4K20m3的减少,这是细胞转化的标志,在感染高适应性HCV时具有重要意义,但在感染基础适应性病毒时没有。
在这里,我们提出了两种机制——它们不是相互排斥的——来解释高病毒适应性的影响:早期感染细胞数量的增加,或每个细胞复制更多的RNA分子。引入HCV适应性作为病毒-宿主相互作用的影响的含义,对于肝脏疾病的过程,是有保证的。重点在于HCV介导的肝细胞癌可能被人类肝脏的长期HCV感染所促进。病毒适应性可能会增加的情况。
Cellular epigenetic modifications occur in the course of viral infections. We previously documented that hepatitis C virus (HCV) infection of human hepatoma Huh-7.5 cells results in a core protein-mediated decrease of Aurora kinase B (AURKB) activity and phosphorylation of Serine 10 in histone H3 (H3Ser10ph) levels, with an affectation of inflammatory pathways. The possible role of HCV fitness in infection-derived cellular epigenetic modifications is not known.
Here we approach this question using HCV populations that display a 2.3-fold increase in general fitness (infectious progeny production), and up to 45-fold increase of the exponential phase of intracellular viral growth rate, relative to the parental HCV population.
We show that infection resulted in a HCV fitness-dependent, average decrease of the levels of H3Ser10ph, AURKB, and histone H4 tri-methylated at Lysine 20 (H4K20m3) in the infected cell population. Remarkably, the decrease of H4K20m3, which is a hallmark of cellular transformation, was significant upon infection with high fitness HCV but not upon infection with basal fitness virus.
Here we propose two mechanisms ─which are not mutually exclusive─ to explain the effect of high viral fitness: an early advance in the number of infected cells, or larger number of replicating RNA molecules per cell. The implications of introducing HCV fitness as an influence in virus-host interactions, and for the course of liver disease, are warranted. Emphasis is made in the possibility that HCV-mediated hepatocellular carcinoma may be favoured by prolonged HCV infection of a human liver, a situation in which viral fitness is likely to increase.