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研究揭示具有自发控制HIV1个体的不同病毒库
2020-08-27 15:16

美国麻省理工学院和哈佛大学Xu G. Yu小组近日取得一项新成果。经过不懈努力,他们揭示了具有自发控制HIV-1个体的不同病毒库。 2020年8月26日,《自然》在线发表了这一成果。

在本研究中,使用二代测序对近乎完整的单个HIV-1基因组和相应染色体整合位点的研究表明,超级控制者的原病毒库经常由完整原病毒序列的寡克隆或近单克隆簇组成。与接受长期抗逆转录病毒治疗的个体相反,来自超级控制者的完整前病毒序列被整合到人类基因组的不同位点,并且优先整合到着丝粒卫星DNA或19号染色体上与克鲁勃相关含锌指结构域的基因中,两者均与异染色质形成相关。

而且,来自超级控制者的完整原病毒序列整合位点与宿主基因组转录起始位点相近以及染色质可及距离增加,并且富含抑制性染色质标记。这些数据表明,前病毒库的独特构型表征了自然病毒控制的结构相关性,病毒库的质量而非数量可能是区别功能治愈HIV-1感染的重要特征。

此外,尽管分析了一个超级控制者超过15亿个外周血单个核细胞,研究人员仍无法检测到完整的前病毒序列,这增加了对HIV-1感染进行无菌治疗的可能性,以前仅在同种异体造血干细胞移植之后才观察到,并且这在极少数情况下可能是可行的。

研究人员表示,尽管存在具有复制能力的病毒库,但仅有不到0.5%的感染者(以下称为“超级控制者”)可以实现对HIV-1复制的持续、无药物控制。诱导这种自发维持且无法检测血浆病毒血症的能力是HIV-1治疗研究的主要目标,但是具有这种调控能力的前病毒库特征仍有待确定。

附:英文原文

Title: Distinct viral reservoirs in individuals with spontaneous control of HIV-1

Author: Chenyang Jiang, Xiaodong Lian, Ce Gao, Xiaoming Sun, Kevin B. Einkauf, Joshua M. Chevalier, Samantha M. Y. Chen, Stephane Hua, Ben Rhee, Kaylee Chang, Jane E. Blackmer, Matthew Osborn, Michael J. Peluso, Rebecca Hoh, Ma Somsouk, Jeffrey Milush, Lynn N. Bertagnolli, Sarah E. Sweet, Joseph A. Varriale, Peter D. Burbelo, Tae-Wook Chun, Gregory M. Laird, Erik Serrao, Alan N. Engelman, Mary Carrington, Robert F. Siliciano, Janet M. Siliciano, Steven G. Deeks, Bruce D. Walker, Mathias Lichterfeld, Xu G. Yu

Issue&Volume: 2020-08-26

Abstract: 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 reservoir1. 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 transplantation2,3, may be feasible in rare instances.

DOI: 10.1038/s41586-020-2651-8

Source: https://www.nature.com/articles/s41586-020-2651-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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