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.IMPORTANCE 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.

中文翻译：

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组蛋白脱乙酰基酶抑制剂Suberoylanilide异羟肟酸抑制人类腺病毒基因表达和复制。

人腺病毒（HAdV）在大多数患者中引起较小的疾病，但可能导致小儿，老年和免疫功能低下的人严重疾病甚至死亡。目前尚无批准的抗病毒疗法可用于治疗这些由HAdV引起的严重疾病。在这项研究中，我们显示泛组蛋白脱乙酰基酶（HDAC）抑制剂SAHA降低了组织培养物中的HAdV-5基因表达和DNA复制，最终降低了被感染细胞的病毒产量。重要的是，SAHA还降低了更具毒力和临床相关血清型（包括HAdV-4和HAdV-7）的基因表达。除SAHA以外，其他几种HDAC抑制剂（例如曲古抑菌素A，阿皮西定和panobinostat）也影响HAdV基因的表达。我们确定I类HDAC活性（主要是HDAC2）的丧失会损害病毒基因的有效表达，并且E1A与HDAC2进行物理交互。我们的结果表明，HDAC活性对于HAdV复制是必需的，这可能代表了HAdV诱导的疾病的新药理学靶标。重要提示尽管人腺病毒（HAdV）可以导致某些人群致命的严重疾病，但尚无有效的治疗方法对抗HAdV感染。在这项研究中，我们确定了泛组蛋白脱乙酰基酶（HDAC）抑制剂SAHA对几种与临床相关的HAdV血清型具有抑制活性。这种经美国食品药品监督管理局批准的化合物会影响病毒生命周期的各个阶段，甚至在低浓度下也会降低病毒产量。我们进一步报告I类HDAC活性，特别是HDAC2，是溶菌感染期间有效表达病毒基因所必需的。