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A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

ABSTRACT: 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.

SUBMITTER: Bartha I

PROVIDER: S-EPMC3807812 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

Bartha István I Carlson Jonathan M JM Brumme Chanson J CJ McLaren Paul J PJ Brumme Zabrina L ZL John Mina M Haas David W DW Martinez-Picado Javier J Dalmau Judith J López-Galíndez Cecilio C Casado Concepción C Rauch Andri A Günthard Huldrych F HF Bernasconi Enos E Vernazza Pietro P Klimkait Thomas T Yerly Sabine S O'Brien Stephen J SJ Listgarten Jennifer J Pfeifer Nico N Lippert Christoph C Fusi Nicolo N Kutalik Zoltán Z Allen Todd M TM Müller Viktor V Harrigan P Richard PR Heckerman David D Telenti Amalio A Fellay Jacques J

eLife 20131029

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 cla ...[more]

PMID: 24171102

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Project description:BackgroundInfection with human immunodeficiency virus type 1 (HIV) typically results from transmission of a small and genetically uniform viral population. Following transmission, the virus population becomes more diverse because of recombination and acquired mutations through genetic drift and selection. Viral intrahost genetic diversity remains a major obstacle to the cure of HIV; however, the association between intrahost diversity and disease progression markers has not been investigated in large and diverse cohorts for which the majority of the genome has been deep-sequenced. Viral load (VL) is a key progression marker and understanding of its relationship to viral intrahost genetic diversity could help design future strategies for HIV monitoring and treatment.MethodsWe analysed deep-sequenced viral genomes from 2,650 treatment-naive HIV-infected persons to measure the intrahost genetic diversity of 2,447 genomic codon positions as calculated by Shannon entropy. We tested for associations between VL and amino acid (AA) entropy accounting for sex, age, race, duration of infection, and HIV population structure.ResultsWe confirmed that the intrahost genetic diversity is highest in the env gene. Furthermore, we showed that mean Shannon entropy is significantly associated with VL, especially in infections of >24 months duration. We identified 16 significant associations between VL (p-value<2.0x10-5) and Shannon entropy at AA positions which in our association analysis explained 13% of the variance in VL. Finally, equivalent analysis based on variation in HIV consensus sequences explained only 2% of VL variance.ConclusionsOur results elucidate that viral intrahost genetic diversity is associated with VL and could be used as a better disease progression marker than HIV consensus sequence variants, especially in infections of longer duration. We emphasize that viral intrahost diversity should be considered when studying viral genomes and infection outcomes.Trial registrationSamples included in this study were derived from participants who consented in the clinical trial, START (NCT00867048) (23), run by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). All the participant sites are listed here: http://www.insight-trials.org/start/my_phpscript/participating.php?by=site.

Dataset Information

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

Publications

A genome-to-genome analysis of associations between human genetic variation, HIV-1 sequence diversity, and viral control.

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