基于系统发育重建和时空动态的HIV-1 CRF01_AE毒株的分子流行病学研究
发布时间：2018-11-01 18:47
【摘要】：分子流行病学对于疫苗设计及病原体的治疗评价有重要意义。快速分离和鉴定HIV的新技术以及不断发展的基因系统进化分析方法,为研究病原体起源及传播过程提供了非常有用的工具。事实上,HIV高度的基因变异非常需要在高危群体或不同流行区域间进行成功的系统进化重建。HIV-1 CRF01_AE是第五个引起广泛流行的HIV病毒株以及最早的HIV流行重组株。在亚洲特别是中国不断增强的CRF01-AE毒株流行,以及该毒株伴随着广泛存在高危行为,提醒我们需要全面了解其分子流行病学,后者无论对治疗预防及疫苗开放均有着重要意义。因此,本研究对亚洲特别是中国地区流行的CRF01_AE毒株序列进行了一个全面的多基因系统进化和亲缘地理学研究。首先,为了更好的理解全球和亚洲毒株之间的进化关系,为了探索CRF01_AE毒株在中国的流行传播史,我们通过利用基因系统进化和贝叶斯因子方法学,分析了全球范围内包括中国在内的15个国家的1957株HIV-1 CRF01_AE毒株的gag p17序列。我们的结果证明了来自泰国、越南和中国的CRF01_AE毒株之间亲密的进化关系。有意思的是,我们发现了HIV-1 CRF01_AE毒株在中国存在着多个相互独立的传播路线和相互无明显传播关联的变异株,这些可能来自于泰国或者越南,亦或两者兼有。云南省曾被认为是中国毒株最早的发源地,同广西、福建和辽宁省一起被认为存在着最早期的流行簇。然而,这些早期流行簇显示了独立的和主要的动态传播事件,其大致的发生时间介于1991年至2003年之间。其次为了阐述CRF01 AE毒株在中国的传播路线图,我们利用HIV-1两个主要基因位点(比如gag和env)进行贝叶斯进化地理学分析来回顾原始株和变异株的关系。为了达到这个目的。我们一共收集了357条序列(其中gag141条,nv CDS216条)。这些序列代表了11个国家和中国的11个省份。序列被全部纳入分析数据中,并用BEAST软件描绘出CRF01-AE毒株在中国最有可能的地理传播路线。为了证实我们分析的结果,我们追溯了中国及世界范围的HIV-1流行病史的相关文献报道。我们的分析为CRF01-AE从进入中国到分布到内陆提供了更为详细的动态过程,包括时间和空间。这些分析结果明确指出中非共和国是毒株最早的发源地,并于1982年进入到泰国,1992年进入到越南以及随后的中国。其中传播到中国最有可能的是两条路线。第一条线路是通过缅甸从泰国传到云南,并有少量传播到福建和海南。然而,目前尚缺乏来自缅甸的序列来进一步证实该路线。有意思的第二条线路,从越南到广西,广西在这边线路作为次级发源地。云南和广西省在病毒向东传播(比如广东、福建和江苏)的路线上扮演着重要的角色,并随后扩散至其他省份(比如辽宁)。第三,通过对来自全球env V3序列资料库的8个不同流行区域的HIV-1CRF01_AE毒株序列做全面分析,该重组毒株间的序列异质性被充分认识到。该研究证明了不同的流行区域间毒株氨基酸序列的不同与之前描述的基因序列不同之间存在着显著差异。亚洲流行株间广泛存在的7个显著模型被发现和证实。其中4个模型主要包括中国变异株,其主要特征为序列的高频率和更高的熵值。这些应用的方法会使人关注到被现在的亚型命名系统所忽视的亚种群异质性。对这些差异的理解将能更好的从队列和地理来阐述补充HIV-1的序列数据库。本次试验的模型能够更好的阐述基因型和表现型之间的关系从而为HIV亚型的治疗和疫苗设计打下良好的基础。综上所述,将系统进化和分子流行病的数据结合能够为CRFO1_AE毒株的深层理解和鉴定提供一个强有力的工具,从而更有效的监控与预防其传播。
[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.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.91
本文编号：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.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：R512.91
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