Dandri Maura, Murray John M, Lutgehetmann Marc, Volz Tassilo, Lohse Ansgar W, Petersen Joerg
Department of Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Hepatology. 2008 Oct;48(4):1079-86. doi: 10.1002/hep.22469.
Analysis of hepatitis B virus (HBV) kinetics with mathematical models may disclose new aspects of HBV infection and host response mechanisms. To determine the kinetics of virion decay from the blood of patients in different phases of chronic infection, we applied mathematical modeling to real-time polymerase chain reaction assays, which enable quantification of viremia and intrahepatic HBV productivity by measuring both copy number and activity of covalently closed circular DNA (relaxed circular DNA/covalently closed circular DNA) in the liver of 80 untreated chronically active HBV carriers (38 hepatitis B e antigen [HBeAg]-positive and 42 HBeAg-negative individuals). We found that the half-life of circulating virions is very fast (median 46 and 2.5 minutes in HBeAg-positive and HBeAg-negative individuals, respectively) and strongly related to viremia, with clearance rates significantly accelerating as viral loads decrease. To investigate whether immune components can influence the kinetics of virion decay, we analyzed viral dynamics in immunodeficient urokinase-type plasminogen activator chimera mice. Virion half-life in mice (range, 44 minutes to >4 hours) was comparable to estimates determined in high viremic carriers, implying that clearance rates in these patients are mostly determined by common nonspecific mechanisms. Notably, the lack of correlation between virion half-life and viremia in mice indicated that immune components significantly accelerate virion clearance rates in individuals with low titers.
Our analyses suggest that both host defense mechanisms and levels of circulating virions affect the kinetics of HBV decay assessed in the serum of chronic carriers. Identification of the factors affecting clearance rates will be important for future antiviral drug developments and it may give insights into the mechanisms involved in clearance of other chronic infections, such as human immunodeficiency virus and hepatitis C virus.
用数学模型分析乙型肝炎病毒（HBV）动力学可能会揭示HBV感染和宿主反应机制的新方面。为了确定慢性感染不同阶段患者血液中病毒粒子的衰变动力学，我们将数学模型应用于实时聚合酶链反应检测，该检测通过测量80例未经治疗的慢性活动性HBV携带者（38例乙型肝炎e抗原[HBeAg]阳性和42例HBeAg阴性个体）肝脏中共价闭合环状DNA（松弛环状DNA/共价闭合环状DNA）的拷贝数和活性，能够定量病毒血症和肝内HBV产生率。我们发现循环病毒粒子的半衰期非常短（HBeAg阳性和HBeAg阴性个体的中位数分别为46分钟和2.5分钟），并且与病毒血症密切相关，随着病毒载量的降低，清除率显著加快。为了研究免疫成分是否能影响病毒粒子的衰变动力学，我们分析了免疫缺陷尿激酶型纤溶酶原激活剂嵌合小鼠的病毒动力学。小鼠体内病毒粒子的半衰期（范围为44分钟至>4小时）与高病毒血症携带者的估计值相当，这意味着这些患者的清除率主要由常见的非特异性机制决定。值得注意的是，小鼠体内病毒粒子半衰期与病毒血症之间缺乏相关性，这表明免疫成分在低滴度个体中显著加快了病毒粒子的清除率。
我们的分析表明，宿主防御机制和循环病毒粒子水平均会影响慢性携带者血清中评估的HBV衰变动力学。确定影响清除率的因素对于未来抗病毒药物的开发很重要，并且可能有助于深入了解其他慢性感染（如人类免疫缺陷病毒和丙型肝炎病毒）清除过程中涉及的机制。
