Defective hepatitis B virus DNA is not associated with disease status but is reduced by polymerase mutations associated with drug resistance
Defective hepatitis B virus DNA is not associated with disease status but is reduced by polymerase mutations associated with drug resistance
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DOI：
10.1002/hep.22386
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发表时间：
2008-09-01
期刊：
影响因子：
13.5
通讯作者：
Revill, Peter A.
中科院分区：
文献类型：
--
作者：
Preiss, Scott;Littlejohn, Margaret;Revill, Peter A.
乙型肝炎病毒DNA （dDNA）缺陷是由剪接的乙型肝炎病毒（HBV）基因组前信使RNA （pgRNA）反向转录而成，并已在慢性乙型肝炎（CH-B）患者中发现。主要的2.2 kb剪接pgRNA通过聚合酶内的缺失和帧移位编码一种新的HBV基因产物，乙肝剪接蛋白（HBSP）。虽然剪接RNA和HBSP表达与HBV DNA水平升高和肝纤维化相关，但DNA在HBV相关疾病中的作用在很大程度上尚不明确。我们的目的是：(1)比较一系列HBV感染血清样本中DNA的相对比例（% dDNA），包括人类免疫缺陷病毒(HIV)/HBV合并感染患者和具有不同严重程度肝病的HBV单感染患者，以及(2)确定与耐药性相关的突变对缺陷DNA产生的影响。在90%的CH-B患者中检测到DNA缺陷。在单感染组和HIV/ hbv共感染组之间，dna的相对丰度没有显著差异。我们还发现% DNA与丙氨酸转氨酶、乙型肝炎e抗原状态、HBV DNA水平、纤维化水平、代偿性或失代偿性肝硬化、基因型或药物治疗之间没有关联。然而，与野生型HBV相比，拉米夫定耐药（LW-R） HBV感染个体的% DNA显著降低（P < 0.0001），这表明抗病毒药物耐药性改变了DNA缺陷和基因组长度之间的平衡。循环。利用HBV编码LMV-R突变的体外实验证实了这些结果。结论：我们的研究结果未发现dna与疾病状态相关参数之间存在关联，并提示dna的相对丰度在很大程度上取决于HBV聚合酶的完整性，与肝脏疾病的严重程度无关。
Defective hepatitis B virus DNA (dDNA) is reverse-transcribed from spliced hepatitis B virus (HBV) pregenomic messenger RNA (pgRNA) and has been identified in patients with chronic HBV (CH-B). The major 2.2-kb spliced pgRNA encodes a novel HBV gene product, the hepatitis B splice protein (HBSP) via a deletion and frame shift within the polymerase. Although spliced RNA and HBSP expression have been associated with increased HBV DNA levels and liver fibrosis, the role of dDNA in HBV-associated disease is largely undefined. Our aims were to (1) compare the relative proportions of dDNA (% dDNA) in a range of HBV-infected serum samples, including patients with human immunodeficiency virus (HIV)/HBV coinfection and HBV-monoinfected persons with differing severities of liver disease, and (2) determine the effect of mutations associated with drug resistance on defective DNA production. Defective DNA was detected in 90% of persons with CH-B. There was no significant difference in the relative abundance of dDNA between the monoinfected and HIV/HBV-coinfected groups. We also found no association between the % dDNA and alanine aminotransferase, hepatitis B e antigen status, HBV DNA levels, fibrosis levels, compensated or decompensated fiver cirrhosis, genotype, or drug treatment. However, the % dDNA was significantly lower in individuals infected with lamivudine-resistant (LW-R) HBV compared with wild-type HBV (P < 0.0001), indicating that antiviral drug resistance alters the balance between defective and genomic length DNA in. circulation. Experiments in vitro using HBV encoding LMV-R mutations confirmed these results. Conclusion: Our results identified no association between dDNA and parameters associated with disease status and suggested that the relative abundance of dDNA is largely dependent on the integrity of the HBV polymerase and is unrelated to the severity of liver disease.