Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
J Virol. 2019 May 15;93(11). doi: 10.1128/JVI.00181-19. Print 2019 Jun 1.
Innate immunity is the first line of host defense against viral invasion. The induction of type I interferons (IFNs) and inflammatory cytokines is essential to host antiviral immune responses, which are also key targets of viral immune evasion. Human cytomegalovirus (HCMV) can establish long-term latent infections, in which immune evasion is a pivotal step. In this study, we identified HCMV protein UL44, a DNA polymerase processivity factor, as an inhibitor of the interferon regulatory factor 3 (IRF3)- and NF-κB-dependent antiviral response. Ectopic expression of UL44 inhibited HCMV-triggered induction of downstream effector genes and enhanced viral replication. Conversely, knockdown of UL44 potentiated HCMV-triggered induction of downstream antiviral genes. UL44 interacted with IRF3 and p65, and it inhibited the binding of IRF3 and NF-κB to the promoters of their downstream antiviral genes. These findings reveal an important mechanism of immune evasion by HCMV at the transcriptional level. Induction of type I IFNs and inflammatory cytokines plays pivotal roles in host antiviral innate immune responses. Viruses have evolved various mechanisms to interfere with these processes. HCMV causes severe ailments in immunodeficient populations and is a major cause of birth defects. It has been shown that HCMV antagonizes host innate immune defenses, which is important for establishing immune evasion and latent infection. In this study, we identified the HCMV DNA polymerase subunit UL44 as a suppressor of antiviral innate immune responses. Overexpression of UL44 impaired HCMV-triggered induction of type I IFNs and other antiviral genes and thus potentiated viral replication, whereas UL44 deficiency showed opposite effects. Mechanistic studies indicated that UL44 acts by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes. These findings defined an important mechanism of HCMV immune evasion at the transcriptional level, which may provide a therapeutic target for the treatment of HCMV infection.
先天免疫是宿主抵御病毒入侵的第一道防线。诱导 I 型干扰素（IFN）和炎症细胞因子对于宿主抗病毒免疫反应至关重要，这也是病毒免疫逃避的关键靶点。人类巨细胞病毒（HCMV）可以建立长期潜伏感染，其中免疫逃避是一个关键步骤。在这项研究中，我们鉴定了 HCMV 蛋白 UL44，一种 DNA 聚合酶延伸因子，是干扰素调节因子 3（IRF3）和 NF-κB 依赖性抗病毒反应的抑制剂。UL44 的异位表达抑制了 HCMV 触发的下游效应基因的诱导，并增强了病毒复制。相反，UL44 的敲低增强了 HCMV 触发的下游抗病毒基因的诱导。UL44 与 IRF3 和 p65 相互作用，并抑制 IRF3 和 NF-κB 与它们下游抗病毒基因启动子的结合。这些发现揭示了 HCMV 在转录水平上进行免疫逃避的重要机制。I 型 IFN 和炎症细胞因子的诱导在宿主抗病毒先天免疫反应中起着关键作用。病毒已经进化出各种机制来干扰这些过程。HCMV 在免疫缺陷人群中引起严重疾病，是出生缺陷的主要原因。已经表明 HCMV 拮抗宿主先天免疫防御，这对于建立免疫逃避和潜伏感染很重要。在这项研究中，我们鉴定了 HCMV DNA 聚合酶亚基 UL44 作为抗病毒先天免疫反应的抑制剂。UL44 的过表达损害了 HCMV 触发的 I 型 IFN 和其他抗病毒基因的诱导，从而增强了病毒复制，而 UL44 的缺乏则表现出相反的效果。机制研究表明，UL44 通过抑制 IRF3 和 NF-κB 与下游抗病毒基因启动子的结合来发挥作用。这些发现定义了 HCMV 免疫逃避的一个重要机制，这可能为治疗 HCMV 感染提供一个治疗靶点。
