title: Whole genome sequencing of SIV-infected macaques identifies candidate loci that may contribute to host control of virus replication.
abstract: BACKGROUND
  A 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Our 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.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ericsen
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.forename: Justin M
authors.initials: JM
authors.lastname: Greene
authors.forename: Michael
authors.initials: M
authors.lastname: Lauck
authors.forename: Muthuswamy
authors.initials: M
authors.lastname: Raveendran
authors.forename: David Rio
authors.initials: DR
authors.lastname: Deiros
authors.forename: Mariel S
authors.initials: MS
authors.lastname: Mohns
authors.forename: Nicolas
authors.initials: N
authors.lastname: Vince
authors.forename: Brian T
authors.initials: BT
authors.lastname: Cain
authors.forename: Ngoc H
authors.initials: NH
authors.lastname: Pham
authors.forename: Jason T
authors.initials: JT
authors.lastname: Weinfurter
authors.forename: Adam L
authors.initials: AL
authors.lastname: Bailey
authors.forename: Melisa L
authors.initials: ML
authors.lastname: Budde
authors.forename: Roger W
authors.initials: RW
authors.lastname: Wiseman
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Rogers
authors.forename: David H
authors.initials: DH
authors.lastname: O'Connor
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000821:virology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D016679:Genome, Viral; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008251:Macaca / Q000235:genetics / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D014779:Virus Replication / Q000235:genetics*