Distinct viral reservoirs in individuals with spontaneous control of HIV-1.
Distinct viral reservoirs in individuals with spontaneous control of HIV-1.
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DOI：
10.1038/s41586-020-2651-8
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发表时间：
2020-09
期刊：
影响因子：
64.8
通讯作者：
Yu XG
中科院分区：
文献类型：
--
作者：
Jiang C;Lian X;Gao C;Sun X;Einkauf KB;Chevalier JM;Chen SMY;Hua S;Rhee B;Chang K;Blackmer JE;Osborn M;Peluso MJ;Hoh R;Somsouk M;Milush J;Bertagnolli LN;Sweet SE;Varriale JA;Burbelo PD;Chun TW;Laird GM;Serrao E;Engelman AN;Carrington M;Siliciano RF;Siliciano JM;Deeks SG;Walker BD;Lichterfeld M;Yu XG
尽管存在有复制能力的病毒储库，但在不到0.5%的感染个体（此处称为“精英感染者”）中自然实现了对HIV-1复制的持续、无药物控制。诱导这种自发维持不可检测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库的特征仍有待确定。在这里，使用下一代测序的近全长单HIV-1基因组和相应的染色体整合位点，我们表明，前病毒水库的精英控制器经常组成的寡克隆到近单克隆集群的完整前病毒序列。与接受长期抗逆转录病毒治疗的个体相反，精英控制者的完整前病毒序列整合在人类基因组中高度不同的位点，并优先位于着丝粒卫星DNA或19号染色体上含有Krüppel相关框结构域的锌指基因中，这两者都与异染色质特征相关。此外，完整的前病毒序列从精英控制器的整合位点显示出增加的距离转录起始位点和可访问的宿主基因组的染色质，并在抑制染色质标记丰富。这些数据表明，一个独特的配置的前病毒水库代表了天然病毒控制的结构相关性，和病毒水库的质量，而不是数量，可以是一个重要的区别特征的HIV-1感染的功能性治愈。此外，在一个精英控制器中，尽管分析了超过15亿个外周血单核细胞，我们仍无法检测到完整的前病毒序列，这提高了以前仅在异基因造血干细胞移植后观察到的HIV-1感染的灭菌治疗在罕见情况下可能是可行的。
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.
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影响因子：
15.9
作者：
Chen, Huabiao;Li, Chun;Lichterfeld, Mathias
通讯作者：
Lichterfeld, Mathias
影响因子：
4.4
作者：
Affinito, Ornella;Palumbo, Domenico;Cocozza, Sergio
通讯作者：
Cocozza, Sergio
影响因子：
64.5
作者：
Ho YC;Shan L;Hosmane NN;Wang J;Laskey SB;Rosenbloom DI;Lai J;Blankson JN;Siliciano JD;Siliciano RF
通讯作者：
Siliciano RF
影响因子：
6.7
作者：
Kauder SE;Bosque A;Lindqvist A;Planelles V;Verdin E
通讯作者：
Verdin E
影响因子：
30.8
作者：
Corces, M. Ryan;Buenrostro, Jason D.;Wu, Beijing;Greenside, Peyton G.;Chan, Steven M.;Koenig, Julie L.;Snyder, Michael P.;Pritchard, Jonathan K.;Kundaje, Anshul;Gkeenleaf, William J.;Majeti, Ravindra;Chang, Howard Y.
通讯作者：
Chang, Howard Y.