Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
J Virol. 2019 May 29;93(12). doi: 10.1128/JVI.00088-19. Print 2019 Jun 15.
Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease. Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.
人腺病毒（HAdV）在大多数患者中引起轻微疾病，但可导致儿科、老年科和免疫功能低下个体发生严重疾病和死亡。目前尚无针对这些严重 HAdV 诱导疾病的批准抗病毒疗法。在这项研究中，我们表明泛组蛋白去乙酰化酶（HDAC）抑制剂 SAHA 可降低组织培养中 HAdV-5 的基因表达和 DNA 复制，最终降低感染细胞中的病毒产量。重要的是，SAHA 还降低了包括 HAdV-4 和 HAdV-7 在内的更具毒性和临床相关血清型的基因表达。除了 SAHA 之外，其他几种 HDAC 抑制剂（例如，曲古抑菌素 A、阿比西定和帕比司他）也影响 HAdV 基因表达。我们确定 I 类 HDAC 活性的丧失（主要是 HDAC2）会损害病毒基因的有效表达，并且 E1A 与 HDAC2 发生物理相互作用。我们的结果表明，HDAC 活性是 HAdV 复制所必需的，这可能代表 HAdV 诱导疾病的新的药理学靶标。尽管人腺病毒（HAdV）可引起严重疾病，在某些人群中可能致命，但目前尚无有效的治疗方法来对抗 HAdV 感染。在这项研究中，我们确定泛组蛋白去乙酰化酶（HDAC）抑制剂 SAHA 对几种临床相关的 HAdV 血清型具有抑制活性。这种美国食品和药物管理局批准的化合物会影响病毒生命周期的各个阶段，即使在低浓度下也能降低病毒产量。我们进一步报告说，I 类 HDAC 活性，特别是 HDAC2，在裂解感染过程中对病毒基因的有效表达是必需的。对 SAHA 介导的 HAdV 基因表达和复制抑制的机制的研究将增强我们对病毒-细胞相互作用的现有认识，并有助于开发毒性更低、更有效的抗病毒药物来治疗 HAdV 感染。
