Superinfection with woodchuck hepatitis virus strain WHVNY of livers chronically infected with strain WHV7.
Superinfection with woodchuck hepatitis virus strain WHVNY of livers chronically infected with strain WHV7.
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土拨鼠肝炎病毒 WHVNY 株重复感染慢性感染 WHV7 株的肝脏。
DOI：
10.1128/jvi.02361-14
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发表时间：
2015
影响因子：
5.4
通讯作者：
Gudima,SeverinO
中科院分区：
文献类型：
--
作者：
Rodrigues,Louise;Freitas,Natalia;Kallakury,BhaskarV;Menne,Stephan;Gudima,SeverinO
维持慢性嗜肝DNA病毒感染的决定因素尚未完全了解。B型肝炎病毒（HBV）研究领域中一个长期悬而未决的争论表明，在慢性嗜肝DNA病毒感染期间，嗜肝DNA病毒的细胞间传播至少是非常低效的（如果发生的话），病毒重叠感染是不太可能的事件，并且慢性嗜肝DNA病毒感染可以在没有病毒传播的情况下仅通过受感染肝细胞的分裂来维持。先前对鸭HBV显示了重叠感染排除，但对HBV或HBV相关的土拨鼠肝炎病毒（WHV）未显示。三只土拨鼠，这是慢性感染的菌株WHV 7和已经开发的WHV诱导的肝细胞癌（HCC），与另一种WHV株，WHVNY重叠感染。重复感染后6周，处死土拨鼠，检查肝脏和HCC组织。通过使用WHV毒株特异性PCR测定和（i）在从所有重叠感染动物收集的血清样品中发现在重叠感染后第1 - 6周期间的WHVNY松弛环状DNA，（ii）在从三只重叠感染的土拨鼠收集的肝脏和HCC的组织样品中检测复制衍生的WHVNY RNA，和（iii）在重复感染后收获的组织中发现WHVNY DNA复制中间体。结果与慢性感染期间持续但低效的嗜肝DNA病毒细胞间传播和重复感染的发生一致，并表明在慢性感染的肝脏中重复感染的嗜肝DNA病毒所占据的复制空间是有限的。在慢性嗜肝DNA病毒感染的机制的背景下讨论的结果。IMPORTANCEThis研究旨在更好地了解慢性嗜肝DNA病毒感染的维持的决定因素。生成的数据表明，在慢性感染土拨鼠肝炎病毒的肝脏中，（i）嗜肝DNA病毒重复感染和细胞间传播可能继续发生，（ii）病毒传播显然效率低下，这与肝脏中有限数量的细胞促进嗜肝DNA病毒传播的解释一致。细胞间病毒传播的局限性很可能是在细胞水平上介导的，并不反映病毒的特性。我们的研究结果进一步推进了对慢性嗜肝DNA病毒感染机制的理解。持续但有限的嗜肝DNA病毒传播和重复感染对维持慢性感染状态的意义应在后续研究中进一步评估，以确定阻断病毒传播是否有助于抑制慢性嗜肝DNA病毒感染。
The determinants of the maintenance of chronic hepadnaviral infection are yet to be fully understood. A long-standing unresolved argument in the hepatitis B virus (HBV) research field suggests that during chronic hepadnaviral infection, cell-to-cell spread of hepadnavirus is at least very inefficient (if it occurs at all), virus superinfection is an unlikely event, and chronic hepadnavirus infection can be maintained exclusively via division of infected hepatocytes in the absence of virus spread. Superinfection exclusion was previously shown for duck HBV, but it was not demonstrated for HBV or HBV-related woodchuck hepatitis virus (WHV). Three woodchucks, which were chronically infected with the strain WHV7 and already developed WHV-induced hepatocellular carcinomas (HCCs), were superinfected with another WHV strain, WHVNY. Six weeks after the superinfection, the woodchucks were sacrificed and tissues of the livers and HCCs were examined. The WHVNY superinfection was demonstrated by using WHV strain-specific PCR assays and (i) finding WHVNY relaxed circular DNA in the serum samples collected from all superinfected animals during weeks one through six after the superinfection, (ii) detecting replication-derived WHVNY RNA in the tissue samples of the livers and HCCs collected from three superinfected woodchucks, and (iii) finding WHVNY DNA replication intermediates in tissues harvested after the superinfection. The results are consistent with the occurrence of continuous but inefficient hepadnavirus cell-to-cell spread and superinfection during chronic infection and suggest that the replication space occupied by the superinfecting hepadnavirus in chronically infected livers is limited. The findings are discussed in the context of the mechanism of chronic hepadnavirus infection.IMPORTANCEThis study aimed to better understand the determinants of the maintenance of chronic hepadnavirus infection. The generated data suggest that in the livers chronically infected with woodchuck hepatitis virus, (i) hepadnavirus superinfection and cell-to-cell spread likely continue to occur and (ii) the virus spread is apparently inefficient, which is consistent with the interpretation that a limited number of cells in the livers facilitates the spread of hepadnavirus. The limitations of the cell-to-cell virus spread most likely are mediated at the level of the cells and do not reflect the properties of the virus. Our results further advance the understanding of the mechanism of chronic hepadnavirus infection. The significance of the continuous but limited hepadnavirus spread and superinfection for the maintenance of the chronic state of infection should be further evaluated in follow-up studies in order to determine whether blocking the virus spread would facilitate the suppression of chronic hepadnavirus infection.