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

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

Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques

“…As expected KIR1D and KIR3D sequences were recovered that had been characterized previously but we were unable to detect any KIR2DL4 sequences. To investigate whether this reflected variation within the binding sites of primers for KIR2DL4 transcripts, we compared our original primer sequences against genomic sequences from 62 total WGS and MES MCM samples (Supplementary Table 2) (Ericsen et al 2014). In order to distinguish KIR2DL4 -specific reads from other KIRs, raw genomic sequence reads were mapped onto a complete genomic Mamu-KIR2DL4 sequence extracted from a bacterial artificial chromosome (bRH-242L13, accession# BX842591) sequenced by Sambrook et al (2005).…”

“…WGS datasets from 18 MCM were generated in a previous study (Supplementary Table 2) (Ericsen et al 2014). Briefly, genomic DNA was isolated from PBMCs and Illumina paired-end libraries were constructed following standard protocol (complete description available at http://www.hgsc.bcm.edu).…”

Discovery of novel MHC-class I alleles and haplotypes in Filipino cynomolgus macaques (Macaca fascicularis) by pyrosequencing and Sanger sequencing

“…Many of these diseases and treatment outcomes are influenced by polymorphisms of the major histocompatibility complex (MHC), a genomic region that encodes the MHC transplantation and immune regulatory molecules Shiina et al 2004). In this regard, information on the diversity of the MHC alleles and haplotypes may provide an internal genetic control to better define the factors of disease susceptibility and immunity and help to maximize the power of the small study sizes and minimize a priori bias and the effect of heterozygosity in the macaque disease study groups (Arikata et al 2012;Ericsen et al 2014;Vallender 2014).…”

Exome sequences of toque macaques (Macaca sinica) of Sri Lanka reveal many amino acid changes

“…We used eight macaque genomes to compare with toque macaque exome data; three M. mulatta (SRR1927155, SRR1929293, SRR1950974) (Xue et al 2016), one Vietnamese M. fascicularis (SRA023855) (Yan et al 2011), one Malaysian M. fascicularis (Higashino et al 2012), two Mauritian M. fascicularis (SRR1564753, SRR1564755) (Ericsen et al 2014), and one M. thibetana (SRR1024051) (Fan et al 2014). These 8 individuals (section 2.3) were used separately for variant calling to determine effects of SNPs on genes of all 7 individuals except reference.…”