Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
J Virol. 2018 Jun 29;92(14). doi: 10.1128/JVI.00298-18. Print 2018 Jul 15.
Cancer-causing herpesviruses infect nearly every human and persist indefinitely in B lymphocytes in a quiescent state known as latency. A hallmark of this quiescence or latency is the presence of extrachromosomal viral genomes with highly restricted expression of viral genes. Silencing of viral genes ensures both immune evasion by the virus and limited pathology to the host, yet how multiple genes on multiple copies of viral genomes are simultaneously silenced is a mystery. In a unifying theme, we report that both cancer-causing human herpesviruses, despite having evolved independently, are silenced through the activities of two members of the Krüppel-associated box (KRAB) domain-zinc finger protein (ZFP) (KRAB-ZFP) epigenetic silencing family, revealing a novel STAT3-KRAB-ZFP axis of virus latency. This dual-edged antiviral strategy restricts the destructive ability of the lytic phase while promoting the cancer-causing latent phase. These findings also unveil roles for KRAB-ZFPs in silencing of multicopy foreign genomes with the promise of evicting herpesviruses to kill viral cancers bearing clonal viral episomes. Despite robust immune responses, cancer-causing viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist for life. This persistence is accomplished partly through a stealth mechanism that keeps extrachromosomal viral genomes quiescent. Quiescence, or latency, ensures that not every cell harboring viral genomes is killed directly through lytic activation or indirectly via the immune response, thereby evicting virus from host. For the host, quiescence limits pathology. Thus, both virus and host benefit from quiescence, yet how quiescence is maintained through silencing of a large set of viral genes on multiple viral genomes is not well understood. Our studies reveal that members of a gene-silencing family, the KRAB-ZFPs, promote quiescence of both cancer-causing human viruses through simultaneous silencing of multiple genes on multicopy extrachromosomal viral genomes.
致癌疱疹病毒几乎感染了每一个人，并以潜伏状态在静止的 B 淋巴细胞中无限期存在。这种静止或潜伏的一个标志是存在具有高度受限的病毒基因表达的染色体外病毒基因组。病毒基因的沉默确保了病毒的免疫逃逸和宿主的有限病理损伤，但如何同时沉默多个病毒基因组上的多个基因仍然是一个谜。在一个统一的主题中，我们报告说，尽管致癌的人类疱疹病毒是独立进化的，但它们都是通过两个 KRAB 结构域-锌指蛋白（ZFP）（KRAB-ZFP）表观遗传沉默家族成员的活性而沉默的，揭示了病毒潜伏的新型 STAT3-KRAB-ZFP 轴。这种双重抗病毒策略限制了裂解期的破坏性能力，同时促进了致癌潜伏期。这些发现还揭示了 KRAB-ZFPs 在沉默多拷贝外源基因组中的作用，有望驱逐疱疹病毒，以杀死带有克隆病毒外源性染色体的病毒癌。尽管存在强大的免疫反应，但致癌病毒 EBV 和 Kaposi 肉瘤相关疱疹病毒（KSHV）会终生持续存在。这种持续存在部分是通过一种保持染色体外病毒基因组静止的隐身机制来实现的。静止或潜伏确保了并非每个携带病毒基因组的细胞都通过裂解激活或通过免疫反应间接直接被杀死，从而将病毒从宿主中驱逐出去。对于宿主来说，静止限制了病理。因此，病毒和宿主都从静止中受益，但如何通过沉默多个病毒基因组上的大量病毒基因来维持静止状态尚不清楚。我们的研究揭示了基因沉默家族的成员，KRAB-ZFPs，通过同时沉默多个多拷贝染色体外病毒基因组上的基因来促进两种致癌人类病毒的静止。
