Transcription and replication of a natural hepatitis B virus nucleocapsid promoter variant is regulated in vivo by peroxisome proliferators
Transcription and replication of a natural hepatitis B virus nucleocapsid promoter variant is regulated in vivo by peroxisome proliferators
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DOI：
10.1006/viro.2001.1169
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发表时间：
2001-10-25
期刊：
影响因子：
3.7
通讯作者：
McLachlan, A
中科院分区：
文献类型：
--
作者：
Raney, AK;Kline, EF;McLachlan, A
已经产生了一种乙型肝炎病毒（HBV）转基因小鼠，其核衣壳启动子（A1764T + G1766A）含有天然突变，可抑制类视黄醇X受体α (RXR α)和过氧化物酶体增殖物激活受体α (PPAR α)异源二聚体与近端核激素受体识别序列的结合。病毒的转录和复制发生在肝脏和肾脏。核衣壳启动子突变不能阻止过氧化物酶体增殖体在这些变异HBV转基因小鼠肝脏中增加病毒转录和复制。这表明过氧化物酶体增殖物可能通过HBV基因组增强子1区域的核激素受体识别位点，以PPAR α依赖的方式直接增强病毒转录。肝细胞核因子4 （HNF4）与核衣壳启动子中近端核激素受体识别序列的结合似乎限制了转录起始位点前RNA的合成。因此，与野生型HBV转基因小鼠相比，变异HBV转基因小鼠转录非常少的前RNA，分泌极低水平的乙型肝炎e抗原（HBeAg）。这与表达HBeAg的病毒在感染个体中从HBeAg阳性血清转化为抗hbe抗体阳性状态时优先被消除的建议一致，留下HBeAg表达降低的逃逸HBV变体。(C) 2001学术出版社。
A hepatitis B virus (HBV) transgenic mouse containing a naturally occurring mutation in the nucleocapsid promoter (A1764T plus G1766A) that inhibits the retinoid X receptor alpha (RXR alpha) plus peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimer from binding to the proximal nuclear hormone receptor recognition sequence has been generated. Viral transcription and replication occur in the liver and kidney. The nucleocapsid promoter mutation does not prevent peroxisome proliferators from increasing viral transcription and replication in the liver of these variant HBV transgenic mice. This suggests that peroxisome proliferators may enhance viral transcription directly in a PPAR alpha -dependent manner through the nuclear hormone receptor recognition site in the enhancer 1 region of the HBV genome. Hepatocyte nuclear factor 4 (HNF4) binding to the proximal nuclear hormone receptor recognition sequence in the nucleocapsid promoter appears to limit RNA synthesis from the precore transcription initiation site. Consequently, the variant HBV transgenic mice transcribe very little precore RNA and secrete extremely low levels of hepatitis B e antigen (HBeAg) compared with the wild-type HBV transgenic mice. This is consistent with the suggestion that viruses expressing HBeAg are preferentially eliminated in infected individuals when they seroconvert from HBeAg positive to anti-HBe antibody-positive status, leaving escape HBV variants that have reduced HBeAg expression. (C) 2001 Academic Press.