Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Hepatology. 2012 Jul;56(1):76-85. doi: 10.1002/hep.25663. Epub 2012 Apr 25.
Hepatitis delta virus (HDV) is a natural subviral agent of human hepatitis B virus (HBV). HDV enhances liver damage during concomitant infection with HBV. The molecular pathogenesis of HDV infection remains poorly understood. To advance our understanding of the relationship between HDV infection and liver cancer, it was determined whether HDV could infect in vivo the cells of hepadnavirus-induced hepatocellular carcinoma (HCC). Woodchucks (Marmota monax) that were chronically infected with HBV-related woodchuck hepatitis virus (WHV) and already developed HCCs were used as an experimental model. The locations of HCCs within the livers were determined using ultrasound imaging followed by open surgery. One week after surgery the WHV carrier woodchucks were superinfected with WHV-enveloped HDV (wHDV). Six weeks later the animals were sacrificed and HDV replication in normal liver tissues and in center masses of HCCs was evidenced by Northern analysis, real-time polymerase chain reaction assay, and immunohistochemistry. Based on accumulation levels of HDV RNAs and numbers of infected cells, the efficiency of wHDV infection appears to be comparable in most HCCs and normal liver tissues.
Cells of WHV-induced HCCs are susceptible to HDV infection in vivo, and therefore express functional putative WHV receptors and support the steps of the attachment/entry governed by the hepadnavirus envelope proteins. Because others previously hypothesized that hepadnavirus-induced HCCs are resistant to reinfection with a hepadnavirus in vivo, our data suggest that if such a resistance exists it likely occurs via a block at the post-entry step. The demonstrated ability of HDV to infect already formed HCCs may facilitate development of novel strategies further dissecting the mechanism of liver pathogenesis associated with HDV infection.
乙型肝炎病毒（HBV）的天然亚病毒因子是乙型肝炎病毒（HBV）。HDV 在与 HBV 同时感染时会增强肝损伤。HDV 感染的分子发病机制仍知之甚少。为了深入了解 HDV 感染与肝癌之间的关系，确定 HDV 是否可以在体内感染乙型肝炎病毒引起的肝细胞癌（HCC）的细胞。慢性感染 HBV 相关的地松鼠肝炎病毒（WHV）并已发展为 HCC 的地松鼠（Marmota monax）被用作实验模型。使用超声成像和开放性手术确定肝脏中 HCC 的位置。手术后一周，WHV 携带者地松鼠被 WHV 包膜的 HDV（wHDV）超感染。六周后，处死动物，通过 Northern 分析、实时聚合酶链反应检测和免疫组织化学检测证明正常肝组织和 HCC 中心质量中存在 HDV 复制。基于 HDV RNA 的积累水平和感染细胞的数量，wHDV 感染的效率在大多数 HCC 和正常肝组织中似乎是可比的。
WHV 诱导的 HCC 细胞易于体内感染 HDV，因此表达功能性潜在的 WHV 受体，并支持由肝病毒包膜蛋白控制的附着/进入步骤。因为其他人之前假设肝病毒诱导的 HCC 对体内再次感染肝病毒具有抗性，我们的数据表明，如果存在这种抗性，它可能是通过在进入后步骤发生阻断。HDV 已证明能够感染已形成的 HCC，这可能有助于进一步剖析与 HDV 感染相关的肝脏发病机制的新策略的发展。
