摘要
目前中国HIV-1的流行传播主要由四种亚型推动，分别是CRF07_BC,CRF08_BC, CRF01_AE亚型以及B'亚型。其中B'亚型在中国HIV-1疫情的发展中扮演着比较特殊的角色。B'亚型最初发现于泰国吸毒人群中，并随后扩散到周围的缅甸，马来西亚，印度以及中国的吸毒人群中。B'亚型同时还是六种流行重组亚型的重要组成部分，包括CRF07_BC， CRF08_BC，CRF15_01B，CRF34_01B，CRF33_01B以及CRF48_01B。
最近的研究表明B'毒株是中国中原地区HIV-1在既往献血人群中(Formerplasma donors, PFDs)快速传播的起始毒株。据2005年统计，90年代早期到中期通过献血途径感染HIV-1的报告人数为约为70，000。感染最严重的几个省份依次为河南，安徽，湖北，山东和山西。而最近的研究表明，在该地区HIV-1正在由高危人群向普通人群尤其是异性性活动人群扩散。
近期，最新的动态系统发育学和分子钟理论的方法被广泛用于重建某一流行疾病的流行历史和起源时间的计算等。1989年，云南省瑞丽市在静脉吸毒人群(injecting drug user, IDU)中筛查出146例HIV-1感染者，这是我国境内首次爆发的HIV-1疫情，表明HIV已在我国开始流行。分子流行病学调查结果表明，该人群流行的HIV-1毒株为B'毒株。上世纪90年代中期，我国中原地区因不规范采血导致既往献浆(血)人群(former plasma donor, FPD)大量感染HIV-1病毒。随后的研究发现，该毒株同样是B'亚型毒株，这是HIV-1B'毒株在我国境内引发的另一流行。最近的一项相关研究表明在中原地区既往献血人群中流行的HIV-1B'亚型毒株相对于金三角地区流行的B'毒株形成独立的流行簇，这表明其与金三角地区早期的B'毒株流行有紧密关系。但是上世纪90年代中期在我国中原地区由B'毒株引起的疫情与最早发现于我国云南地区由B'亚型毒株引起的疫情之间是否存在内在关联并不清楚。其次最早发现于我国云南地区的B'亚型毒株的来源也并不清楚。第三，B'亚型毒株最初经由何种方式在我国中原地区进行传播以及后续如何进行扩散也未进行深入的探讨。
为探讨HIV-1B'亚型毒株在中国的起源，进化历史和当下的流行态势，本研究利用47条1993-2009年间来自泰国，缅甸和中国11个省份的B'亚型近全长基因组序列(near full-length genomes，NFLGs)。通过Bayesian分子钟理论对新获得的NFLGs序列进行分析，推算其最近共同祖先株的起源时间(time of the mostrecent common ancestor, tMRCA)，利用合并理论并结合现场流行病学数据重建subtype B'在中国时间-空间的进化过程。同时在近全长基因组研究的基础上，对不同的基因区进行分析，比较不同基因去结果的差异，发现可以吻合近全长基因组的结果的基因区，以节省成本和资源。
研究结果发现，subtype B'在中国可以分为两组。一组主要由采样于云南省的静脉吸毒人群构成(B'YN)，并且在进化树上位于中国B'亚型毒株群体的根部。另一组主要由中国云南省以外的其它省份主要为中原地区来源的既往献血感染人群和异性性传播人群序列组成(B'CN*)，同时还包括少量的男男同性恋人群，静脉吸毒人群等。B'YN和B'CN*的最近共同祖先株的起源时间分别为1985年(1983-1987)和1989年(1987-1991)。本研究同时还计算了B'亚型毒株在亚洲的起源时间(B'TH)为1983年(1981-1985)。通过重建B'亚型毒株在亚洲地区的流行史显示其在90年代中期在中国中部地区引起了HIV-1的快速流行。本研究表明中国中原地区B'亚型毒株在既往献血人群和异性性传播人群中的流行起源于中国云南省静脉吸毒人群。河南是B'亚型毒株在中国中原地区扩散的中心，云南省在金三角地区早期B'亚型毒株的流行与中国中原地区B'亚型毒株在既往献血人群和异性性传播人群中的流行起到了一个桥梁作用。
B'亚型毒株不同基因区分析的结果表明，pol基因系统进化分析的结果与近全长基因组系统进化分析的结果相类似，可以分辨出B'CN*，B'YN，B'TH这三个进化簇，具有较高的分辨率，且流行起始时间的顺序一致。而其他几个基因区，vif, env, nef基因可以将B'CN*与B'YN和B'TH区分开，但不能区分开B'YN与B'TH，至于gag，vpr，vpu基因则不能区分这三个进化簇。基因特征性位点分析发现，pol基因所具有的特征性位点在所有的基因之中是最多的，这可能也是其具有最高分辨率的原因。
本研究探讨了HIV-1B'亚型毒株在中国的输入、变异和扩散的特点与规律，并预测了其发展趋势，无论对于揭示HIV-1B'亚型毒株遗传变异的基本科学问题还是对控制HIV-1感染流行的防治实践都具有理论指导和实用价值。
The HIV-1epidemic in China is primarily driven by four major strains, includingCRF07_BC, CRF08_BC, CRF01_AE, and subtype B'(the Thailand variant ofsubtype B is also referred as to Thai B. Among these HIV-1strains, subtype B' playsunique roles in the genesis of the HIV-1epidemic in China. HIV-1subtype B' wasoriginally identified among injecting drug users (IDUs) in Thailand and subsequentlydisseminated into IDUs populations in neighboring regions, including Myanmar,Malaysia, Eastern India and China. HIV-1subtype B' is also a component of all6circulating recombinant forms (CRFs) known to date that have emerged in Asia:CRF07_BC and CRF08_BC identified in China; CRF15_01B and CRF34_01Bidentified in Thailand; CRF33_01B and CRF48_01B identified in Malaysia.
It is found that HIV-1subtype B' is a single founding strain responsible for HIV-1outbreaks among former plasma donors (FPDs) in central China. In2005, about70,000people who were living with HIV-1at the time had been infected throughunhygienic plasma collection from the early to mid-1990s. The most heavily affectedprovinces include Henan, Anhui, Hubei, Shandong, Shanxi and Shaanxi in centralChina. Recent studies showed that HIV-1subtype B' infections were identified amongother populations, especially among heterosexuals, in central China.
Recently-developed phylogenetic and molecular clock methods have been usedto reconstruct the epidemic history and to estimate the time of the most recentcommon ancestors (tMRCAs). These evolutionary analyses foster understanding of thegenesis of global and regional HIV-1epidemics. The recent study by Li et al.demonstrated that the subtype B' strains responsible for outbreaks among FPDs incentral China formed a distinct monophyletic subcluster within subtype B' andsuggested that subtype B' epidemic among FPDs in central China is most closelyassociated with the early epidemics among IDUs in the Golden Triangle, a majorheroine production area where the boundaries of Myanmar, Laos and Thailand meet.However, details on the precise migration of the HIV-1subtype B' to FPDs andheterosexuals in central China were yet to be unearthed.
To investigate the origin and evolutionary history of HIV-1subtype B' responsible for the epidemic among injecting drug users (IDUs), former plasmadonors (FPDs) and the subsequent heterosexual transmission in China, a total of47sequences of subtype B' near full-length genomes (NFLGs) from Thailand, Myanmarand11provinces across China during1998-2009were used. The NFLGs weresubjected to Bayesian molecular clock analyses to estimate the time of the mostrecent common ancestors (tMRCA) and to reconstitute the time-space process ofsubtype B' dissemination in China combined epidemic data.
The study revealed that subtype B' strains in China can be classified into twodistinct subgroups: i) a monophyletic B' cluster (B'CN*) consisting of subtype B'sequences mainly from FPDs and heterosexuals across China outside of Yunnan; ii)B' strains circulating among IDUs in Yunnan (B'YN) that occupy the most basalposition of B' clade in China. The tMRCAof B'YN and B'CN*were estimated to be1985(1982-1987) and1989(1987-1991) respectively. At the same time, the tMRCAofB'YN was estimated to be1983(1981-1985). The skyline plot profile revealed theexplosive nature of subtype B' expansion in central China in the mid-1990s. Ourresults suggest that subtype B' epidemics among FPDs and heterosexuals in inlandChina were most likely originated from a single founding subtype B' strain that hadbeen circulating among IDUs in Yunnan province. Henan province was an epidemiccenter during the spread of HIV-1subtype B' in central China. Yunnan province playsa pivotal role in bridging the pre-existing subtype B' epidemics in Southeast Asia withthe subsequent epidemic among FPDs and heterosexuals in inland China.
The near full-length genomes of subtype B' were divided into different singlegenes and put into phylogenetic analyses. The phylogenetic analyses of partialfragments showed that pol gene have similar results with that of the near full-lengthgenomes. It can separate the three clusters B'CN*，B'YN and B'TH with highposterior probability. As to other genes, vif, env, nef can separate B'CN*from B'YNand B'TH, but can't separate B'YN from B'TH. The gag，vpr，vpu gene can't separateany of the three clusters. After analyses of signature amino acid sites of each gene,pol gene was found to have the highest number of signature amino acid sites amongthese genes. That should be one of the reasons that pol gene have the highestresolution.
This study investigated the input, evolution and spread of HIV-1subtype B' inChina and predicted the future trends of this epidemic. It helps to reveal the basicscientific questions of HIV-1evolution and provide reference to the control andprevention of HIV-1epidemic.
引文
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