2012-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/649108摘要：B型肝炎是全世界最常見的感染源之一，根據世界衛生組織的報告全世界約有三億五千萬個帶原者。其中亞洲東南部以及非洲地區約占了總數的四分之三。在台灣帶原者比例大約是百分之十五到二十，換成人口數約為三到四百萬人。這些帶原者往往並不自覺遭受感染，以至於發現時已經形成肝硬化或是肝癌。雖然目前已經有保護作用很好的疫苗，但是對於已感染B型肝炎的人仍然需要更積極以及有效的治療方式。慢性B型肝炎的進程可以分為三個階段(1)一段很長的免疫容忍期(immune tolerance phase)，這時血液中有高濃度的病毒量，並可偵測到e抗原，但是肝功能以及組織都正常。(2)免疫廓清期(immune clearance phase)，這時會有間歇性的肝發炎，臨床上丙氨酸轉氨酶(ALT)之指數升高，最後e抗原消失，產生e抗體。(3)DNA嵌入期(DNA integration phase)，血液中病毒下降，ALT恢復正常。若是成人感染HBV，則沒有免疫容忍期，直接進入免疫廓清期。對於流行病學家而言，病毒在人類族群中以及個體內的起源，散佈以及演化是一個重要的課題。針對C型肝炎以及HIV病毒的研究已證實，病毒的演化特性包含突變率，演化速度，變異性等等，與疾病的進程有很大的關聯性。在HIV的研究中，病毒改變的模式甚至可作為後續疾病進程的一個預測因子。相關的研究在B型肝炎病毒則是非常的缺乏。尤其以台灣而言，患者往往是出生即遭受感染。在這漫長的免疫容忍期中，病毒的演進與日後疾病的進程的關係仍然付之闕如。因此本研究將利用台大醫院小兒科過去所收集的病例中，找出從感染B型肝炎早期(早於十歲)追蹤至今超過15年的慢性B型肝炎病患的血清檢體，分析不同時間點血液中B型肝炎的序列，以期了解病毒在免疫容忍期的改變模式。這樣的研究有助於吾人了解面性B肝患者中早期病毒的演化模式以及其和後續疾病進程的關係。<br> Abstract: Hepatitis B virus (HBV) is one of the most common infectious agents in the world. According to world health organization (WHO), more than a third of the world’s population (2 billion people) has been infected with HBV. Of these, 350 million people worldwide are chronic carriers. Prevalence of chronic hepatitis B in south-east Asia and subSaharan Africa areas is 10-20%. In Taiwan, 15-20% of the population is chronic HBV carriers which translate to 3.5-4 million people nation-wide. One of the distinctive features of HBV infection is that the course of disease is largely influenced by the age of acquiring. The progress of chronic hepatitis B can be divided into three phases based on virus-host interactions (1) a long immune tolerance phase with nearly normal histology, high concentrations of HBV DNA in the serum, and positive HBeAg; (2) the immune clearance stage with the emergence of antibody against HBeAg accompanied by inflammation and fibrosis and fluctuating serum alanine transaminase concentration; (3) and DNA integration and tolerance phase with low concentration of HBV DNA and normal alanine transaminase level. For those who are infected during adulthood, there is no immune tolerance phase. Instead, the disease goes directly to immune clearance phase in a short period of time. The study of the origins, progress, and impact of viral infections in human populations has long been of interest to epidemiologists and is the most active and productive areas of research in evolutionary biology. While viral evolution has been established as important in the pathogenesis of chronic viral disease in hepatitis C virus (HCV) and HIV, little is known about viral evolution in chronic HBV. Because HBV uses reverse transcriptase in replication, the error-prone nature of polymerase may make the viral dynamics more close to RNA virus rather than DNA virus. So far, most studies on chronic HBV viral evolution have focused on relative late stage, i.e. during or after immune clearance stage, which usually does not occur until two decades of HBV infection. How HBV progress during the first two decades within a host is largely unknown. Nevertheless, studies on HIV and HCV have shown that viral evolution at early stage of infection is important for understanding the pathogenesis of disease. In addition, many viral parameters that are important for epidemiology of HBV, such as effect population size within hosts, mutation rate, and population growth rate, cannot be accessed without such information. To study viral behavior in chronic hepatitis B, we aim to focus on viral evolution at relative "early" stage of infection. Evolutionary dynamics of HBV will be estimated using an established Bayesian Markov chain Monte Carlo (MCMC) approach that incorporates the time of viral sampling. This approach estimates the rate of nucleotide change and dynamics of population genetic diversity through time. Based on above analyses, a population genetic model that describes how the demographic history of HBV population will be established. These knowledge are important for HBV epidemiology and can be used to infer viral epidemic behavior.B型肝炎演化突變率