A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.
A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.
复制标题
人类遗传变异，HIV-1序列多样性和病毒控制之间关联的基因组到基因组分析。
DOI：
10.7554/elife.01123
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发表时间：
2013-10-29
期刊：
影响因子：
7.7
通讯作者：
Fellay J
中科院分区：
文献类型：
--
作者：
Bartha I;Carlson JM;Brumme CJ;McLaren PJ;Brumme ZL;John M;Haas DW;Martinez-Picado J;Dalmau J;López-Galíndez C;Casado C;Rauch A;Günthard HF;Bernasconi E;Vernazza P;Klimkait T;Yerly S;O'Brien SJ;Listgarten J;Pfeifer N;Lippert C;Fusi N;Kutalik Z;Allen TM;Müller V;Harrigan PR;Heckerman D;Telenti A;Fellay J
HIV-1序列多样性受到宿主基因组因素产生的选择压力的影响。使用来自1071名个体的配对人类和病毒数据，我们进行了超过3000次全基因组扫描，测试宿主DNA多态性，HIV-1序列变异和血浆病毒载量（VL）之间的关联，同时考虑人类和病毒群体结构。我们观察到人类SNP与总共48种HIV-1氨基酸变异显著相关（p<2.4 × 10−12）。所有相关的SNP都映射到HLA I类区域。使用VL结果评估宿主和病原体变异的临床相关性。我们确定了使用病毒变异识别宿主因子的两个关键优势：（1）HIV-1序列变异的关联信号比VL强得多，反映了病毒变异的“中间表型”性质;（2）关联测试可以在没有任何临床数据的情况下运行。建议的基因组对基因组的方法突出了基因组冲突的网站，是一种普遍适用于宿主-病原体相互作用的研究策略。http://dx.doi.org/10.7554/eLife.01123.001开发艾滋病毒的治疗方法或疫苗具有挑战性，因为病毒的基因组成不断变化，以战胜人类免疫系统。此外，由于人类和微生物的长期共同进化，免疫系统是高度可变的。每个人都会试图以独特的方式对抗入侵的病毒，迫使病毒获得特定的突变，这些突变可以被解释为这种一对一战斗的基因签名。为了探索共同进化对HIV的影响，Bartha等人从1071名感染HIV（艾滋病病毒）的个体中采集了人类和病毒基因组样本，并使用基因分型和测序技术对两者的遗传变异进行了全面描述。然后使用计算技术来搜索人类DNA序列中的变体与病毒序列中的变体之间的联系。在人类基因组中发现的最常见的遗传变异类型是单核苷酸多态性，或简称SNP：当单个核苷酸-A，C，G或T -被不同的核苷酸取代时产生SNP。Bartha等人在他们的研究中发现，人类DNA序列中的SNP与HIV中48个氨基酸的变异有关。此外，所有这些SNP都是在一组称为HLA（人类白细胞抗原）系统的基因中发现的，该系统编码在免疫反应中起重要作用的蛋白质。这项工作确定了人类基因组中对艾滋病病毒施加压力的区域，以及艾滋病病毒逃避人类控制的区域。Bartha等人开发的方法允许通过观察微生物的基因组和感染者的基因组来研究微生物和人类宿主之间的相互作用。它还区分了宿主诱导的突变，这些突变限制了病毒造成伤害的能力，而这些突变是病原体所容忍的。类似的策略可以用于研究其他传染病。DOI：http://dx.doi.org/10.7554/eLife.01123.002网站
HIV-1 sequence diversity is affected by selection pressures arising from host genomic factors. Using paired human and viral data from 1071 individuals, we ran >3000 genome-wide scans, testing for associations between host DNA polymorphisms, HIV-1 sequence variation and plasma viral load (VL), while considering human and viral population structure. We observed significant human SNP associations to a total of 48 HIV-1 amino acid variants (p<2.4 × 10−12). All associated SNPs mapped to the HLA class I region. Clinical relevance of host and pathogen variation was assessed using VL results. We identified two critical advantages to the use of viral variation for identifying host factors: (1) association signals are much stronger for HIV-1 sequence variants than VL, reflecting the ‘intermediate phenotype’ nature of viral variation; (2) association testing can be run without any clinical data. The proposed genome-to-genome approach highlights sites of genomic conflict and is a strategy generally applicable to studies of host–pathogen interaction. DOI: http://dx.doi.org/10.7554/eLife.01123.001 Developing treatments or vaccines for HIV is challenging because the genetic makeup of the virus is constantly changing in an effort to outwit the human immune system. Moreover, the immune system is highly variable as a result of the long-standing co-evolution of humans and microbes. Each individual will try to oppose the invading virus in a unique way, forcing the virus to acquire specific mutations that can be interpreted as the genetic signature of this one-against-one battle. To explore the influence of co-evolution on HIV, Bartha et al. took samples of both human and viral genomes from 1071 individuals infected with HIV, the AIDS virus, and used genotyping and sequencing technology to obtain a comprehensive description of the genetic variation in both. Computational techniques were then used to search for links between variants in the human DNA sequences and variants in the viral sequences. The most common type of genetic variation found in the human genome is a single nucleotide polymorphism, or SNP for short: a SNP is produced when a single nucleotide – an A, C, G or T – is replaced by a different nucleotide. Bartha et al. found that SNPs within the human DNA sequences in their study were linked to variations in 48 amino acids in HIV. Moreover, all these SNPs were found within a group of genes known as the HLA (human leukocyte antigen) system, which encodes for proteins that play a vital role in the immune response. This work identified the areas of the human genome that put pressure on the AIDS virus, and the regions of the virus that serve to escape human control. The approach developed by Bartha et al. allows the interactions between a microbe and a human host to be studied by looking at the genome of the microbe and the genome of the infected person. It also differentiates host-induced mutations that limit the capacity of the virus to do harm from those that are tolerated by the pathogen. A similar strategy could be used to study other infectious diseases. DOI: http://dx.doi.org/10.7554/eLife.01123.002