發(fā)布時間：2018-01-14 05:22

  本文關(guān)鍵詞：HIV-1和HCV在注射吸毒人群的傳播瓶頸和毒株起源　出處：《中國疾病預防控制中心》2017年博士論文　論文類型：學位論文

  更多相關(guān)文章： HIV-1 HCV 注射吸毒 傳播

【摘要】：自1981年艾滋病被發(fā)現(xiàn)以來,艾滋病病毒(Human Immunodeficiency Virus,HIV)已在全球引起7000萬人感染,造成3000多萬人的死亡。丙型肝炎病毒(HCV)在人類中的傳播史已有上百年,被感染人數(shù)超過1.7億。盡管針對HIV和HCV感染治療藥物研發(fā)均獲得重大突破,但疫苗研發(fā)尚未取得明顯的進展。其主要技術(shù)障礙之一是病毒基因組的高變異,進化出了許多機制來逃避免疫攻擊,造成人群傳播。然而,在HIV和HCV感染之初的基因變異很小的時期,成為干預和阻斷傳播的關(guān)鍵時刻,我們稱其為瓶頸期或機遇窗口。因此,研究探索HIV-1和HCV的傳播瓶頸及其規(guī)律,成為尋找疫苗預防靶點的重要研究領(lǐng)域。經(jīng)血傳播是HIV-1和HCV病毒的重要感染途徑之一,注射吸毒共用注射器是其主要表現(xiàn)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。該人群HIV-1的感染率一般為10-30%,HCV的感染率常高達50%及以上,兩種病毒的共感染也很常見。本研究的目的是研究我國IDU中HIV-1和HCV傳播瓶頸及其規(guī)律,獲取傳播/奠基病毒(transmitting/foundervirus,T/Fvirus)的特征和相關(guān)參數(shù),為探索針對性的干預措施和疫苗預防靶點提供數(shù)據(jù)支持和理論指導。本課題借助美國國立衛(wèi)生研究院(NIH)在我國新疆開展的兩個血清學研究隊列,即HIV預防試驗網(wǎng)絡(HPTN) 033和058采集的樣本,用核酸擴增的技術(shù)鑒別其中的HIV-1和HCV早期傳播病例,采用單基因擴增技術(shù)獲得HIV-1和HCV早期感染患者體內(nèi)傳播及奠基病毒準種的核酸序列。對每個個體的傳播及奠基病毒開展以下系統(tǒng)的分析,包括系統(tǒng)進化樹,最近共同祖先株(time of the most recent common ancestor, tMRCA)、Highlighter、泊松分布模型檢驗、貝葉斯分子鐘假設檢驗。通過綜合運用上述方法和建立新的識別模式,得出新疆IDU的HIV-1和HCV T/F病毒的基因復雜度、傳播瓶頸及其特征的參數(shù)。也同時探討T/F病毒傳播相關(guān)的特異性氨基酸位點,分析新疆IDU的HIV-1和HCV病毒的毒株起源。本研究的主要研究結(jié)果如下:1)共獲得60例HIV-1和HCV早期感染者的T/F病毒群的數(shù)據(jù)資料,包括1070條HIV-1 ev序列和770條HCV基因組5'半長區(qū)序列;2)建立了一種直觀地定量T/F病毒的分析方法;3)發(fā)現(xiàn)在IDU中HIV-1的多病毒感染比例為39%,而HCV的多病毒感染比例為52%; 4)新疆IDU中HIV-1流行株為CRF_07BC,起源于云南,起源時間為1992年;5)新疆IDU中HCV主要流行株為1b, 3a和3b。其中1b毒株來源于歐美而非中國南方,起源時間為1990年,晚于中國南方15年;3a與中國南方株有共同的來源,但傳入新疆時間為1973年,晚于南方流行5年;3b來源于中國云南,起源時間約20年前,與HIV-1毒株進入新疆的時間相近;6)新疆IDU中CRF_07BC T/F病毒序列和同性傳播的T/F病毒序列呈現(xiàn)多個傳播途徑相關(guān)的差異化氨基酸位點。將本研究的結(jié)果與既往研究的結(jié)果進行比較可以發(fā)現(xiàn),相比于HIV-1經(jīng)性傳播僅為20%的多病毒感染比例,經(jīng)血傳播的瓶頸更大,達到39%。因而,阻斷HIV-1經(jīng)血傳播的難度更大。比較同為經(jīng)血傳播的瓶頸效應,HCV的多病毒感染比例為52%,明顯高于HIV-1的39%。因而,阻斷HCV傳播的難度較HIV-1更大。該研究從分子生物學角度提示在注射吸毒人群中傳播過程中,HCV具有比較HIV-1更高的感染性和傳播效率。這充分解釋了為什么在HPTN033和HPTN058兩項研究的7年間,HIV-1的新發(fā)感染降低了 4.6倍,HCV只降低了 1.6倍。新疆HIV-1和HCV溯源研究的結(jié)果顯示,HCV在新疆的流行具有更多的基因型別,更復雜的來源和更長的歷史。HCV3b型則很可能是與HIV-1 CRF07_BC毒株一同由注射吸毒人群和毒品貿(mào)易傳新疆的。綜上,本研究利用兩個NIH隊列的寶貴樣本,在國際上首次對HIV-1和HCV在經(jīng)血傳播途徑中的傳播瓶頸進行了比較研究。本研究建立的簡易直觀的判斷傳播瓶頸大小的評價方法,適用于公共衛(wèi)生工作中采集精度不是很高的樣本�？梢詷O大地擴展各類高危人群和環(huán)境下病毒傳播瓶頸這一重要數(shù)據(jù)的收集,促進HIV-1和HCV傳播動力學和疾病自然史的研究,為制定有針對性的精準干預和疫苗預防提供重要的參考和科學的指導。
[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.

【學位授予單位】：中國疾病預防控制中心
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R512.91;R512.63

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