基于系統(tǒng)發(fā)育重建和時空動態(tài)的HIV-1 CRF01_AE毒株的分子流行病學(xué)研究
發(fā)布時間：2018-11-01 18:47
【摘要】：分子流行病學(xué)對于疫苗設(shè)計(jì)及病原體的治療評價有重要意義�？焖俜蛛x和鑒定HIV的新技術(shù)以及不斷發(fā)展的基因系統(tǒng)進(jìn)化分析方法,為研究病原體起源及傳播過程提供了非常有用的工具。事實(shí)上,HIV高度的基因變異非常需要在高危群體或不同流行區(qū)域間進(jìn)行成功的系統(tǒng)進(jìn)化重建。HIV-1 CRF01_AE是第五個引起廣泛流行的HIV病毒株以及最早的HIV流行重組株。在亞洲特別是中國不斷增強(qiáng)的CRF01-AE毒株流行,以及該毒株伴隨著廣泛存在高危行為,提醒我們需要全面了解其分子流行病學(xué),后者無論對治療預(yù)防及疫苗開放均有著重要意義。因此,本研究對亞洲特別是中國地區(qū)流行的CRF01_AE毒株序列進(jìn)行了一個全面的多基因系統(tǒng)進(jìn)化和親緣地理學(xué)研究。首先,為了更好的理解全球和亞洲毒株之間的進(jìn)化關(guān)系,為了探索CRF01_AE毒株在中國的流行傳播史,我們通過利用基因系統(tǒng)進(jìn)化和貝葉斯因子方法學(xué),分析了全球范圍內(nèi)包括中國在內(nèi)的15個國家的1957株HIV-1 CRF01_AE毒株的gag p17序列。我們的結(jié)果證明了來自泰國、越南和中國的CRF01_AE毒株之間親密的進(jìn)化關(guān)系。有意思的是,我們發(fā)現(xiàn)了HIV-1 CRF01_AE毒株在中國存在著多個相互獨(dú)立的傳播路線和相互無明顯傳播關(guān)聯(lián)的變異株,這些可能來自于泰國或者越南,亦或兩者兼有。云南省曾被認(rèn)為是中國毒株最早的發(fā)源地,同廣西、福建和遼寧省一起被認(rèn)為存在著最早期的流行簇。然而,這些早期流行簇顯示了獨(dú)立的和主要的動態(tài)傳播事件,其大致的發(fā)生時間介于1991年至2003年之間。其次為了闡述CRF01 AE毒株在中國的傳播路線圖,我們利用HIV-1兩個主要基因位點(diǎn)(比如gag和env)進(jìn)行貝葉斯進(jìn)化地理學(xué)分析來回顧原始株和變異株的關(guān)系。為了達(dá)到這個目的。我們一共收集了357條序列(其中g(shù)ag141條,nv CDS216條)。這些序列代表了11個國家和中國的11個省份。序列被全部納入分析數(shù)據(jù)中,并用BEAST軟件描繪出CRF01-AE毒株在中國最有可能的地理傳播路線。為了證實(shí)我們分析的結(jié)果,我們追溯了中國及世界范圍的HIV-1流行病史的相關(guān)文獻(xiàn)報(bào)道。我們的分析為CRF01-AE從進(jìn)入中國到分布到內(nèi)陸提供了更為詳細(xì)的動態(tài)過程,包括時間和空間。這些分析結(jié)果明確指出中非共和國是毒株最早的發(fā)源地,并于1982年進(jìn)入到泰國,1992年進(jìn)入到越南以及隨后的中國。其中傳播到中國最有可能的是兩條路線。第一條線路是通過緬甸從泰國傳到云南,并有少量傳播到福建和海南。然而,目前尚缺乏來自緬甸的序列來進(jìn)一步證實(shí)該路線。有意思的第二條線路,從越南到廣西,廣西在這邊線路作為次級發(fā)源地。云南和廣西省在病毒向東傳播(比如廣東、福建和江蘇)的路線上扮演著重要的角色,并隨后擴(kuò)散至其他省份(比如遼寧)。第三,通過對來自全球env V3序列資料庫的8個不同流行區(qū)域的HIV-1CRF01_AE毒株序列做全面分析,該重組毒株間的序列異質(zhì)性被充分認(rèn)識到。該研究證明了不同的流行區(qū)域間毒株氨基酸序列的不同與之前描述的基因序列不同之間存在著顯著差異。亞洲流行株間廣泛存在的7個顯著模型被發(fā)現(xiàn)和證實(shí)。其中4個模型主要包括中國變異株,其主要特征為序列的高頻率和更高的熵值。這些應(yīng)用的方法會使人關(guān)注到被現(xiàn)在的亞型命名系統(tǒng)所忽視的亞種群異質(zhì)性。對這些差異的理解將能更好的從隊(duì)列和地理來闡述補(bǔ)充HIV-1的序列數(shù)據(jù)庫。本次試驗(yàn)的模型能夠更好的闡述基因型和表現(xiàn)型之間的關(guān)系從而為HIV亞型的治療和疫苗設(shè)計(jì)打下良好的基礎(chǔ)。綜上所述,將系統(tǒng)進(jìn)化和分子流行病的數(shù)據(jù)結(jié)合能夠?yàn)镃RFO1_AE毒株的深層理解和鑒定提供一個強(qiáng)有力的工具,從而更有效的監(jiān)控與預(yù)防其傳播。
[Abstract]:Molecular epidemiology plays an important role in vaccine design and the therapeutic evaluation of pathogens. Rapid isolation and identification of new technologies for HIV, as well as the evolving analytical methods of gene systems, provide a useful tool for the study of the origin and propagation of pathogens. In fact, genetic variation of HIV height requires a successful systematic evolutionary reconstruction between high-risk populations or different endemic regions. HIV-1CRF01 _ AE is the fifth widely prevalent HIV virus strain and the earliest HIV prevalence recombinant strain. In Asia, especially China's growing CRF01-AE strain, and the widespread high-risk behaviour of the strain, it is important to remind us of the need for a comprehensive understanding of its molecular epidemiology, both for the prevention of treatment and the opening of vaccines. Therefore, the study of CRF01 _ AE strain in Asia, especially in China, has carried out a comprehensive multi-gene system evolution and genetic geography study. First, in order to better understand the evolutionary relationship between the global and Asian strains, in order to explore the history of the epidemic spread of CRF01 _ AE strains in China, we use the genetic system evolution and Bayesian factor methodology. The gag p17 sequence of the 1957 HIV-1CRF01 _ AE strain of 15 countries, including China, was analyzed worldwide. Our results demonstrate an intimate evolutionary relationship between the CRF01 _ AE strains from Thailand, Vietnam and China. Interestingly, we have found that the HIV-1CRF01 _ AE strain is present in China with a number of independent transmission routes and variants associated with each other, which may come from Thailand or Vietnam, or both. Yunnan province has been regarded as the earliest birthplace of Chinese strain, and it is considered the earliest popular cluster in Guangxi, Fujian and Liaoning Province. However, these early pop clusters show independent and major dynamic propagation events, which take place roughly between 1991 and 2003. Secondly, in order to elucidate the road map of CRF01AE strain in China, we use the two major gene sites of HIV-1, such as gag and genetic algorithm, to analyze the relationship between the original strain and the variant strain. for this purpose. We collected 357 sequences altogether (in which gag141, nv CDS216). These sequences represent 11 countries and 11 provinces in China. The sequence was all included in the analysis data and the best possible geographical spread of the CRF01-AE strain in China was traced with the BEAST software. In order to confirm the results of our analysis, we traced the relevant literature reports of the history of the HIV-1 epidemic in China and the world. Our analysis provides a more detailed dynamic process for CRF01-AE from entering China to distribution to inland, including time and space. The results clearly indicated that the Central African Republic was the earliest birthplace of the strain and entered Thailand in 1982 and entered Viet Nam in 1992 and subsequently in China. One of the most likely routes to China is the two routes. The first line is through Myanmar from Thailand to Yunnan and has a small spread to Fujian and Hainan. However, there is still a lack of a sequence from Myanmar to further confirm the route. Interesting second line, from Vietnam to Guangxi, Guangxi in this way as the secondary origin. Yunnan and Guangzhou play an important role in the route of viruses spreading eastward, such as Guangdong, Fujian and Jiangsu, and then spread to other provinces, such as Liaoning. Third, the sequence heterogeneity among the recombinant strains was fully recognized by comprehensively analyzing HIV-1CRF01 _ AE strain sequences from 8 different popular regions of the global V3V3 sequence database. This study demonstrated that there was a significant difference between the differences in the amino acid sequence of the different endemic strains and the different gene sequences previously described. Seven distinct models widely existed among Asian pop plants were found and confirmed. Among them, 4 models mainly include Chinese mutants, whose main features are the high frequency and higher entropy of the sequence. These applications will focus on sub-population heterogeneity that is ignored by the current subtype naming system. Understanding of these differences will provide better access to the sequence database that complements HIV-1 from the queue and geography. The model of this experiment can describe the relationship between genotype and phenotype, thus laying a good foundation for the treatment of HIV subtype and the design of vaccine. In conclusion, the combination of systematic evolution and molecular epidemiological data can provide a powerful tool for deep understanding and identification of CRFO1 _ AE strains, thus more effective monitoring and prevention of the spread of the virus.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R512.91
本文編號：2304781
[Abstract]:Molecular epidemiology plays an important role in vaccine design and the therapeutic evaluation of pathogens. Rapid isolation and identification of new technologies for HIV, as well as the evolving analytical methods of gene systems, provide a useful tool for the study of the origin and propagation of pathogens. In fact, genetic variation of HIV height requires a successful systematic evolutionary reconstruction between high-risk populations or different endemic regions. HIV-1CRF01 _ AE is the fifth widely prevalent HIV virus strain and the earliest HIV prevalence recombinant strain. In Asia, especially China's growing CRF01-AE strain, and the widespread high-risk behaviour of the strain, it is important to remind us of the need for a comprehensive understanding of its molecular epidemiology, both for the prevention of treatment and the opening of vaccines. Therefore, the study of CRF01 _ AE strain in Asia, especially in China, has carried out a comprehensive multi-gene system evolution and genetic geography study. First, in order to better understand the evolutionary relationship between the global and Asian strains, in order to explore the history of the epidemic spread of CRF01 _ AE strains in China, we use the genetic system evolution and Bayesian factor methodology. The gag p17 sequence of the 1957 HIV-1CRF01 _ AE strain of 15 countries, including China, was analyzed worldwide. Our results demonstrate an intimate evolutionary relationship between the CRF01 _ AE strains from Thailand, Vietnam and China. Interestingly, we have found that the HIV-1CRF01 _ AE strain is present in China with a number of independent transmission routes and variants associated with each other, which may come from Thailand or Vietnam, or both. Yunnan province has been regarded as the earliest birthplace of Chinese strain, and it is considered the earliest popular cluster in Guangxi, Fujian and Liaoning Province. However, these early pop clusters show independent and major dynamic propagation events, which take place roughly between 1991 and 2003. Secondly, in order to elucidate the road map of CRF01AE strain in China, we use the two major gene sites of HIV-1, such as gag and genetic algorithm, to analyze the relationship between the original strain and the variant strain. for this purpose. We collected 357 sequences altogether (in which gag141, nv CDS216). These sequences represent 11 countries and 11 provinces in China. The sequence was all included in the analysis data and the best possible geographical spread of the CRF01-AE strain in China was traced with the BEAST software. In order to confirm the results of our analysis, we traced the relevant literature reports of the history of the HIV-1 epidemic in China and the world. Our analysis provides a more detailed dynamic process for CRF01-AE from entering China to distribution to inland, including time and space. The results clearly indicated that the Central African Republic was the earliest birthplace of the strain and entered Thailand in 1982 and entered Viet Nam in 1992 and subsequently in China. One of the most likely routes to China is the two routes. The first line is through Myanmar from Thailand to Yunnan and has a small spread to Fujian and Hainan. However, there is still a lack of a sequence from Myanmar to further confirm the route. Interesting second line, from Vietnam to Guangxi, Guangxi in this way as the secondary origin. Yunnan and Guangzhou play an important role in the route of viruses spreading eastward, such as Guangdong, Fujian and Jiangsu, and then spread to other provinces, such as Liaoning. Third, the sequence heterogeneity among the recombinant strains was fully recognized by comprehensively analyzing HIV-1CRF01 _ AE strain sequences from 8 different popular regions of the global V3V3 sequence database. This study demonstrated that there was a significant difference between the differences in the amino acid sequence of the different endemic strains and the different gene sequences previously described. Seven distinct models widely existed among Asian pop plants were found and confirmed. Among them, 4 models mainly include Chinese mutants, whose main features are the high frequency and higher entropy of the sequence. These applications will focus on sub-population heterogeneity that is ignored by the current subtype naming system. Understanding of these differences will provide better access to the sequence database that complements HIV-1 from the queue and geography. The model of this experiment can describe the relationship between genotype and phenotype, thus laying a good foundation for the treatment of HIV subtype and the design of vaccine. In conclusion, the combination of systematic evolution and molecular epidemiological data can provide a powerful tool for deep understanding and identification of CRFO1 _ AE strains, thus more effective monitoring and prevention of the spread of the virus.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R512.91
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