Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study.
Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study.
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DOI：
10.1016/j.ebiom.2023.104867
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发表时间：
2023-12
期刊：
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
在自然感染的HIV-1中，CCR5(R5)到CXCR4(X4)共受体的转换与更快的艾滋病进展有关，但其机制尚不清楚。阐明最早的X4病毒的进化起源的困难限制了我们对这一现象的理解。我们跟踪了在被确认为急性感染的RV217参与者中传播/创始(T/F)HIV-1的演变。通过单基因组扩增、深度测序和共受体分析，阐明了X4病毒的来源。通过突变证实了与辅受体开关有关的突变。中和试验测定病毒对中和的敏感性。通过对排序后的CD4亚群中的HIV-1RNA进行测序，证明了病毒对CD4亚群的偏好。我们证明了最早的X4病毒是从T/F株从头进化而来的。X4的高使用率可以通过一个单一的突变来实现。负责共受体开关的突变可以逃避中和，并驱动X4变体主要在中央记忆(CM)和幼稚的CD4亚群中复制。可能是由于CM和幼稚亚群的病毒爆发规模较小，X4变体在血浆中以较低的频率存在。X4病毒的起源先于CD4的加速下降。除1例X4病毒外，其余病毒均丢失了保守的V3N301糖链位点。这些发现证明了HIV-1抗原性、辅助受体的使用和CD4亚群靶向的共同进化，这些都对HIV-1的治疗和功能治疗有意义。这些观察结果提供了证据，证明辅助受体开关可以作为免疫逃避的进化机制。人类病毒学研究所、国家卫生研究院、亨利·M·杰克逊军事医学促进基金会、泰国红十字会艾滋病研究中心、吉列德科学公司、默克公司和欢跃医疗公司。
The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.
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DOI：
10.1073/pnas.94.13.6798
发表时间：
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影响因子：
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作者：
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