Estimating the Respective Contributions of Human and Viral Genetic Variation to HIV Control
Publication Date
February 09, 2017
István Bartha, Paul J. Mc Laren, Chanson Brumme, Richard Harrigan, et al
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{"title"=>"Estimating the Respective Contributions of Human and Viral Genetic Variation to HIV Control", "type"=>"journal", "authors"=>[{"first_name"=>"Istv??n", "last_name"=>"Bartha", "scopus_author_id"=>"24334221500"}, {"first_name"=>"Paul J.", "last_name"=>"McLaren", "scopus_author_id"=>"7006020418"}, {"first_name"=>"Chanson", "last_name"=>"Brumme", "scopus_author_id"=>"9274829200"}, {"first_name"=>"Richard", "last_name"=>"Harrigan", "scopus_author_id"=>"56851394600"}, {"first_name"=>"Amalio", "last_name"=>"Telenti", "scopus_author_id"=>"7006764406"}, {"first_name"=>"Jacques", "last_name"=>"Fellay", "scopus_author_id"=>"7801474482"}], "year"=>2017, "source"=>"PLoS Computational Biology", "identifiers"=>{"pui"=>"614671124", "issn"=>"15537358", "scopus"=>"2-s2.0-85014292072", "doi"=>"10.1371/journal.pcbi.1005339", "isbn"=>"1111111111", "sgr"=>"85014292072"}, "id"=>"232a2915-d5ca-3583-889f-14f6048487a0", "abstract"=>"Introduction: Viral load setpoint is a major correlate of HIV disease progression. Genome-wide association studies have identified common human polymorphisms that together explain no more than 15% of its phenotypic variance. Furthermore, studies of the impact of HIV genetic diversity on viral load have produced highly variable estimates. Here we present a joint assessment of the respective contributions of human and viral variation to HIV viral load at setpoint. Methods: Human genotype data across the Major Histocompatibility Complex (MHC) region, full-length consensus HIV sequences and setpoint viral load (pVL) results were available for 1034 treatment naïve individuals of European ancestry, infected with HIV-1 subtype B. Heritability (h2) estimation was carried out with GCTA using three kernel matrices representing: 1) the human Genetic Relatedness Matrix (GRM) derived from the MHC, 2) the viral GRM derived from the full-length sequences, and 3) the sample-specific noise. The human GRM was estimated from 27 common polymorphisms shown to strongly influence viral load selected by LASSO. Bootstrapped phylogenetic trees were inferred from the viral sequences using RAxML after masking out HIV positions that are under significant host selective pressure. The viral GRM was derived from the phylogenetic trees by taking the branch length of the shared ancestry (i.e. the distance from the root to the most recent common ancestor). The estimates were repeated on 30 bootstrap trees and 15 bootstrap replicates of the sample individuals. Clinical site was included as a covariate in the analyses. Results: Estimating the host heritability of HIV pVL using the host GRM alone yielded a median h2 estimate of 8% (IQR=X-(X+1)%) across 15 bootstrap replicates of the samples. The median estimate of pVL h2 drawn from 30 bootstrapped viral trees was 29% (IQR=X-(X+10)%). Combining both the host and viral relatedness matrices showed a comparable viral h2 of 26% (IQR=X-(X+9)%) but a decreased host contribution of 4% (IQR=X-X%). Repeating the estimates on 15 bootstrap replicates of the samples yielded similar results. Discussion: This is the first estimate of the combined and respective contributions of the host and viral genomes to the observed variability of HIV viral load. We showed that both the pathogen and host genomes have detectable impacts on the clinical outcome of infection, which are however not completely independent. In the context of HIV’s strong within-host evolution, these results suggest that the host influence on the virus is a major part of host ability to control clinical outcome.", "link"=>"", "reader_count"=>11, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>2, "Student > Master"=>2, "Student > Bachelor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Researcher"=>5, "Student > Ph. D. Student"=>2, "Student > Master"=>2, "Student > Bachelor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>3, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>7}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}}, "group_count"=>0}

Scopus | Further Information

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