Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
Infectious Disease Division, Brigham and Women's Hospital, Boston, MA, USA.
Nature. 2020 Sep;585(7824):261-267. doi: 10.1038/s41586-020-2651-8. Epub 2020 Aug 26.
Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation, may be feasible in rare instances.
尽管存在具有复制能力的病毒储存库，但在不到 0.5%的受感染个体（此处称为“精英控制者”）中自然实现了对 HIV-1 复制的持续、无药物控制。诱导这种自发维持无法检测到的血浆病毒血症的能力是 HIV-1 治愈研究的主要目标，但精英控制者中前病毒储存库的特征仍有待确定。在这里，我们使用下一代测序技术对接近全长的单个 HIV-1 基因组及其相应的染色体整合位点进行了研究，结果表明，精英控制者的前病毒储存库通常由完整的前病毒序列的寡克隆到近单克隆簇组成。与接受长期抗逆转录病毒治疗的个体相比，来自精英控制者的完整前病毒序列整合到人类基因组中高度不同的位点，并且优先位于着丝粒卫星 DNA 或 19 号染色体上富含 Krüppel 相关盒结构域的锌指基因中，这两者都与异染色质特征相关。此外，来自精英控制者的完整前病毒序列的整合位点与宿主基因组的转录起始位点和可及染色质的距离增加，并且富含抑制性染色质标记。这些数据表明，前病毒储存库的独特结构代表了自然病毒控制的结构相关因素，并且病毒储存库的质量而不是数量可能是 HIV-1 感染功能性治愈的重要区别特征。此外，在一名精英控制者中，尽管分析了超过 15 亿个外周血单核细胞，但我们未能检测到完整的前病毒序列，这增加了一种可能性，即在极少数情况下，先前仅在异基因造血干细胞移植后观察到的 HIV-1 感染的绝育治愈可能是可行的。
