title: HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection.
abstract: Experimental and computational evidence suggests that HLAs preferentially bind conserved regions of viral proteins, a concept we term "targeting efficiency," and that this preference may provide improved clearance of infection in several viral systems. To test this hypothesis, T-cell responses to A/H1N1 (2009) were measured from peripheral blood mononuclear cells obtained from a household cohort study performed during the 2009-2010 influenza season. We found that HLA targeting efficiency scores significantly correlated with IFN-γ enzyme-linked immunosorbent spot responses (P = 0.042, multiple regression). A further population-based analysis found that the carriage frequencies of the alleles with the lowest targeting efficiencies, A*24, were associated with pH1N1 mortality (r = 0.37, P = 0.031) and are common in certain indigenous populations in which increased pH1N1 morbidity has been reported. HLA efficiency scores and HLA use are associated with CD8 T-cell magnitude in humans after influenza infection. The computational tools used in this study may be useful predictors of potential morbidity and identify immunologic differences of new variant influenza strains more accurately than evolutionary sequence comparisons. Population-based studies of the relative frequency of these alleles in severe vs. mild influenza cases might advance clinical practices for severe H1N1 infections among genetically susceptible populations.
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. thertz@fhcrc.org
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: Christine M
authors.initials: CM
authors.lastname: Oshansky
authors.forename: Philippa L
authors.initials: PL
authors.lastname: Roddam
authors.forename: John P
authors.initials: JP
authors.lastname: DeVincenzo
authors.forename: Miguela A
authors.initials: MA
authors.lastname: Caniza
authors.forename: Nebojsa
authors.initials: N
authors.lastname: Jojic
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Phillips
authors.forename: Ian
authors.initials: I
authors.lastname: James
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Halloran
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Lawrence
authors.initials: L
authors.lastname: Corey
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D058501:Enzyme-Linked Immunospot Assay; D005787:Gene Frequency; D006680:HLA Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000453:epidemiology* / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D015233:Models, Statistical; D012044:Regression Analysis
chemical_list: D006680:HLA Antigens; D007371:Interferon-gamma
keywords: HLA association; MHC; Native American; T-cell epitope