HIV-1和HCV在注射吸毒人群的传播瓶颈和毒株起源

发布时间：2018-01-14 05:22

本文关键词：HIV-1和HCV在注射吸毒人群的传播瓶颈和毒株起源　出处：《中国疾病预防控制中心》2017年博士论文　论文类型：学位论文

【摘要】：自1981年艾滋病被发现以来,艾滋病病毒(Human Immunodeficiency Virus,HIV)已在全球引起7000万人感染,造成3000多万人的死亡。丙型肝炎病毒(HCV)在人类中的传播史已有上百年,被感染人数超过1.7亿。尽管针对HIV和HCV感染治疗药物研发均获得重大突破,但疫苗研发尚未取得明显的进展。其主要技术障碍之一是病毒基因组的高变异,进化出了许多机制来逃避免疫攻击,造成人群传播。然而,在HIV和HCV感染之初的基因变异很小的时期,成为干预和阻断传播的关键时刻,我们称其为瓶颈期或机遇窗口。因此,研究探索HIV-1和HCV的传播瓶颈及其规律,成为寻找疫苗预防靶点的重要研究领域。经血传播是HIV-1和HCV病毒的重要感染途径之一,注射吸毒共用注射器是其主要表现形式。因而,注射吸毒人群(IDU) 一直都是HIV-1和HCV感染的高危人群。该人群HIV-1的感染率一般为10-30%,HCV的感染率常高达50%及以上,两种病毒的共感染也很常见。本研究的目的是研究我国IDU中HIV-1和HCV传播瓶颈及其规律,获取传播/奠基病毒(transmitting/foundervirus,T/Fvirus)的特征和相关参数,为探索针对性的干预措施和疫苗预防靶点提供数据支持和理论指导。本课题借助美国国立卫生研究院(NIH)在我国新疆开展的两个血清学研究队列,即HIV预防试验网络(HPTN) 033和058采集的样本,用核酸扩增的技术鉴别其中的HIV-1和HCV早期传播病例,采用单基因扩增技术获得HIV-1和HCV早期感染患者体内传播及奠基病毒准种的核酸序列。对每个个体的传播及奠基病毒开展以下系统的分析,包括系统进化树,最近共同祖先株(time of the most recent common ancestor, tMRCA)、Highlighter、泊松分布模型检验、贝叶斯分子钟假设检验。通过综合运用上述方法和建立新的识别模式,得出新疆IDU的HIV-1和HCV T/F病毒的基因复杂度、传播瓶颈及其特征的参数。也同时探讨T/F病毒传播相关的特异性氨基酸位点,分析新疆IDU的HIV-1和HCV病毒的毒株起源。本研究的主要研究结果如下:1)共获得60例HIV-1和HCV早期感染者的T/F病毒群的数据资料,包括1070条HIV-1 ev序列和770条HCV基因组5'半长区序列;2)建立了一种直观地定量T/F病毒的分析方法;3)发现在IDU中HIV-1的多病毒感染比例为39%,而HCV的多病毒感染比例为52%; 4)新疆IDU中HIV-1流行株为CRF_07BC,起源于云南,起源时间为1992年;5)新疆IDU中HCV主要流行株为1b, 3a和3b。其中1b毒株来源于欧美而非中国南方,起源时间为1990年,晚于中国南方15年;3a与中国南方株有共同的来源,但传入新疆时间为1973年,晚于南方流行5年;3b来源于中国云南,起源时间约20年前,与HIV-1毒株进入新疆的时间相近;6)新疆IDU中CRF_07BC T/F病毒序列和同性传播的T/F病毒序列呈现多个传播途径相关的差异化氨基酸位点。将本研究的结果与既往研究的结果进行比较可以发现,相比于HIV-1经性传播仅为20%的多病毒感染比例,经血传播的瓶颈更大,达到39%。因而,阻断HIV-1经血传播的难度更大。比较同为经血传播的瓶颈效应,HCV的多病毒感染比例为52%,明显高于HIV-1的39%。因而,阻断HCV传播的难度较HIV-1更大。该研究从分子生物学角度提示在注射吸毒人群中传播过程中,HCV具有比较HIV-1更高的感染性和传播效率。这充分解释了为什么在HPTN033和HPTN058两项研究的7年间,HIV-1的新发感染降低了 4.6倍,HCV只降低了 1.6倍。新疆HIV-1和HCV溯源研究的结果显示,HCV在新疆的流行具有更多的基因型别,更复杂的来源和更长的历史。HCV3b型则很可能是与HIV-1 CRF07_BC毒株一同由注射吸毒人群和毒品贸易传新疆的。综上,本研究利用两个NIH队列的宝贵样本,在国际上首次对HIV-1和HCV在经血传播途径中的传播瓶颈进行了比较研究。本研究建立的简易直观的判断传播瓶颈大小的评价方法,适用于公共卫生工作中采集精度不是很高的样本。可以极大地扩展各类高危人群和环境下病毒传播瓶颈这一重要数据的收集,促进HIV-1和HCV传播动力学和疾病自然史的研究,为制定有针对性的精准干预和疫苗预防提供重要的参考和科学的指导。
[Abstract]:Since 1981, AIDS has been found that the AIDS virus (Human Immunodeficiency, Virus, HIV) has infected 70 million people in the world, killing about 30000000 people. The hepatitis C virus (HCV) in human history for hundreds of years, the infected number more than 170 million. Although the HIV and HCV infection in drug development were obtained a major breakthrough, but has not yet made significant progress in vaccine development. One of the main technical barriers is the high variability of the viral genome, have evolved a number of mechanisms to evade immune attack, causing the crowd spread. However, the genetic variation of HIV infection and HCV is very small at the beginning of the period, a crucial time for intervention and blocking transmission. We call it the bottleneck or window of opportunity. Therefore, the bottleneck spread and law research of HIV-1 and HCV, become the important research field for vaccine targets. The blood spread is HIV-1 One of the most important route of infection and HCV virus, drug injection syringe sharing is the main form. Thus, injection drug users (IDU) has always been a high-risk group of HIV-1 and HCV infection in the population. HIV-1 infection rate is generally 10-30%, HCV infection rate is as high as 50% and more than two kinds of viruses were the infection is common. The purpose of this study is to research in China IDU HIV-1 and HCV communication bottleneck and its law, obtain the spread of virus / Foundation (transmitting/foundervirus, T/Fvirus) characteristics and related parameters, in order to explore the measures for prevention and intervention of vaccine targets to provide data support and theoretical guidance. This topic with the National Institutes of Health Research Institute (NIH) in the two cohort in China serological studies in Xinjiang, namely the HIV preventiontrials network (HPTN) 033 and 058 samples, using nucleic acid amplification technology to identify the HIV-1 and HCV in early. Sowing cases, single gene amplification technique of HIV-1 and HCV in patients with early infection and spread of virus nucleic acid sequences for quasi foundation. Analysis of the spread of the virus and the foundation for each individual to carry out the system, including the phylogenetic tree, the most recent common ancestor strains (time of the most recent common ancestor, tMRCA, Highlighter, Poisson) the distribution of model checking, Bias molecular clock hypothesis test. By using the above method and the establishment of new pattern recognition, the HIV-1 and HCV T/F of Xinjiang IDU virus gene complexity, parameters and characteristics of the communication bottleneck. Also discuss the spread of the T/F virus specific amino acids, strain analysis of the origin of Xinjiang IDU HIV-1 and the HCV virus. The main results of this study are as follows: 1) a total of 60 cases of early HIV-1 and HCV infected T/F virus group data, including the 1070 HIV-1 EV sequence The sequence of semi long area column and 770 HCV genome 5'; 2) established a quantitative analysis method of visually T/F virus; 3) found virus infection ratio of HIV-1 in IDU was 39%, and the proportion of HCV virus infection was 52%; 4) in Xinjiang IDU HIV-1 strains CRF_07BC, origin in Yunnan, the origin time is 1992; 5) Xinjiang IDU HCV strains 1b, 3a and 3b. of the 1b strain originated in the United States and non China south, origin time is 1990, after 15 years China south; 3A have a common origin with Chinese south line, but was introduced to Xinjiang in time for the 1973, later than the South the popular 5 years; 3B from Chinese Yunnan, the origin of the time about 20 years ago, similar to HIV-1 strain in Xinjiang time; 6) T/F Xinjiang IDU CRF_07BC virus sequence of T/F virus sequences and homosexual transmission exhibits multiple amino acid transmission related differences in sites. The results of this study and will To compare the results of previous studies can be found, compared to the HIV-1 through sexual transmission is only 20% of the proportion of multiple viral infections, more blood transmission bottleneck, thus reach 39%., blocking blood transmission of HIV-1 is more difficult. Compared with the bottleneck effect for blood borne virus infection, more proportion of HCV was 52%, significantly higher than HIV-1 39%. and HCV, blocking the spread is more difficult than HIV-1 more. The study from the perspective of molecular biology in injection drug users in the process of communication, HCV has a higher HIV-1 infection and transmission efficiency. This fully explains why in the 7 years between HPTN033 and HPTN058 two studies, HIV-1's new hair the infection was reduced by 4.6 times, HCV only decreased by 1.6 times. The HIV-1 of Xinjiang and HCV of the research results showed that the HCV genotype has more popular in Xinjiang, and longer and more complicated history is likely to.HCV3 B Is HIV-1 and CRF07_BC strains together by injecting drug users and the drug trade from Xinjiang. In conclusion, this study uses two NIH queue precious samples, for the first time in the world to spread the bottleneck of HIV-1 and HCV in blood transmission were analyzed. To evaluate the bottleneck spread size method is simple and intuitive established in this study that applies to public health work in the acquisition accuracy is not very high. The sample can greatly expand the collection of the important data of various types of high-risk population and environment virus transmission bottleneck, to promote the study of HIV-1 and HCV transmission dynamics and the natural history of the disease, to develop targeted interventions and accurate vaccination provides an important reference and scientific guidance.

【学位授予单位】：中国疾病预防控制中心
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R512.91;R512.63

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