Whole genome sequencing of SIV-infected macaques identifies candidate loci that may contribute to host control of virus replicationReport as inadecuate




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Genome Biology

, 15:478

Genomics of infectious diseases special issue

Abstract

BackgroundA small percentage of human immunodeficiency virus HIV-infected people and simian immunodeficiency virus SIV-infected macaques control virus replication without antiretroviral treatment. The major determinant of this control is host expression of certain major histocompatibility complex alleles. However, this association is incompletely penetrant, suggesting that additional loci modify the major histocompatibility complex-s protective effect. Here, to identify candidate control-modifying loci, we sequence the genomes of 12 SIV-infected Mauritian cynomolgus macaques that experienced divergent viral load set points despite sharing the protective M1 major histocompatibility complex haplotype.

ResultsOur genome-wide analysis of haplotype-level variation identifies seven candidate control-modifying loci on chromosomes 2, 3, 7, 8, 9, 10, and 14. The highest variant density marks the candidate on chromosome 7, which is the only control-modifying locus to comprise genes with known immunological function. Upon closer inspection, we found an allele for one of these genes, granzyme B, to be enriched in M1+ controllers. Given its established role as a cytotoxic effector molecule that participates in CD8-mediated killing of virus-infected cells, we test the role of variation within gzmb in modifying SIV control by prospectively challenging M1+ granzyme B-defined macaques.

ConclusionsOur study establishes a framework for using whole genome sequencing to identify haplotypes that may contribute to complex clinical phenotypes. Further investigation into the immunogenetics underlying spontaneous HIV control may contribute to the rational design of a vaccine that prevents acquired immune deficiency syndrome.

AbbreviationsAIDSacquired immune deficiency syndrome

bpbase pairs

CMLcontrol-modifying locus

GWASgenome-wide association study

HIVhuman immunodeficiency virus

HLAhuman leukocyte antigen

MCMMauritian cynomolgus macaques

MHCmajor histocompatibility complex

NKnatural killer

PBMCperipheral blood mononuclear cell

PCRpolymerase chain reaction

SIVsimian immunodeficiency virus

SRASequence Read Archive

VCFvariant call format

Electronic supplementary materialThe online version of this article doi:10.1186-s13059-014-0478-z contains supplementary material, which is available to authorized users.

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Author: Adam J Ericsen - Gabriel J Starrett - Justin M Greene - Michael Lauck - Muthuswamy Raveendran - David Rio Deiros - Marie

Source: https://link.springer.com/







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