中缅边境地区复杂HIV-1重组毒株形成机制的进化研究

HIV-1 pandemic in China started from Yunnan, the hardest hit province by HIV-1/AIDS. In particular, high frequency of HIV-1 inter-subtype recombinants was observed in the China-Myanmar border region, and the recombinants are becoming more and more complex. The origin of complicated HIV-1 inter-subtype recombinants is believed to associate with high frequency of co-infection/dual infection with different HIV-1 subtypes, and multiple recombination events among different subtypes and/or some recombinants (intermediates). Our previous study reported a high proportion of HIV-1 dual infection among long-distance truck drivers in this border area, which might be associated with a high proportion of HIV-1 recombinants in this cohort. If multiple recombination events (second/multiple-generation recombination) contribute to the formation of complicated HIV-1 recombinants, the mutual fragments from different recombinants are believed to be genetically related, and able to form a transmission cluster in phylogenetic analysis. To address this hypothesis and investigate the evolutionary mechanism of the origin of complicated recombinants, we will not only conduct cluster and temporal dynamics analyses using the mutual fragments of various recombinants, but also perform phylogenetic analysis of their quasi-species, and compare the recombination patterns and calculate the numbers of recombination breakpoints over time. The results obtained from this project will verify the evolution and transmission association of various HIV-1 recombinants, and elucidate the evolutionary mechanism of origin of the complicated recombinants, which will provide insight into the mechanism of HIV-1 recombination. In addition, the results will also provide valuable information for policy-making on the prevention and control of HIV-1/AIDs in Yunnan and even whole China.

云南是我国HIV-1/AIDS流行的源头和重灾区，特别是在中缅边境地区存在高频的HIV-1亚型间重组，形成了大量复杂重组毒株，其形成机制可能不仅牵涉病毒的共/双感染，也涉及亚型间、甚至重组毒株间反复的二代、多代重组。我们前期在中缅边境长途卡车司机中已经证明重组与高比例的HIV-1双感染有关。如果复杂重组毒株的形成机制牵涉二代或多代重组，那么这些毒株的共有片段必定存在传播上的关联。为了验证该假说，并探明复杂重组的进化起源机制，本研究拟通过对具有共有片段的重组毒株进行聚类分析、时间动力学分析、准种进化分析，同时结合重组位点随时间变化趋势，证明复杂重组株之间的关联，从而揭示该地区高频复杂重组毒株不断产生及形成的进化机制，为深入理解HIV-1重组机制提供基础，并为云南及我国其他地区HIV-1/AIDS防控策略的制定提供科学参考。

在中缅边境地区，HIV-1持续发生高频重组，大量复杂重组毒株的形成机制可能涉及亚型间、甚至重组毒株间反复的二代、多代重组。为了验证该假说，本项目深入分析该地区已报道的所有HIV毒株以及新收集的缅甸、中国云南的HIV样本的亚型流行特性，重组毒株之间的进化、传播关系。结果发现：1）对已报道中缅地区所有HIV毒株序列分析显示，该地区主要以BC重组型的毒株为主，而且重组频率随时间的推移而增加；同时，我们还鉴定了两种新的流行重组型——CRF87_cpx和CRF88_BC，再次证实该地区存在大量复杂重组毒株的事实；2）缅甸籍静脉注射吸毒人群中的HIV毒株能同时与两国的序列形成更为复杂的传播簇，说明该人群在中缅边境地区的HIV-1扩散传播中起重要作用，从而部分揭示了该地区复杂重组毒株形成的外在原因；3）云南省新报告HIV样本中的重组株主要是由早期的HIV流行重组型尤其CRF08_BC、CRF57_BC参与形成的二代、多代重组毒株，该结果在一定程度上解释了中缅边境地区存在复杂重组毒株的内在原因。本研究从内、外因素两个角度揭示中缅边境地区高频复杂重组毒株不断产生及形成的进化机制，加深了对HIV-1重组机制的理解，并为云南及我国其他地区HIV-1/AIDS防控策略的制定提供科学理论依据。