HLA targeting efficiency correlates with human T-cell response magnitude and with mortality from influenza A infection.

Hertz T, Oshansky CM, Roddam PL, DeVincenzo JP, Caniza MA, Jojic N, Mallal S, Phillips E, James I, Halloran ME, Thomas PG, Corey L
Proc Natl Acad Sci U S A. 2013 110 (33): 13492-7

PMID: 23878211 · PMCID: PMC3746844 · DOI:10.1073/pnas.1221555110

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.

MeSH Terms (12)

CD4-Positive T-Lymphocytes Cohort Studies Computational Biology Enzyme-Linked Immunospot Assay Gene Frequency HLA Antigens Humans Influenza, Human Influenza A Virus, H1N1 Subtype Interferon-gamma Models, Statistical Regression Analysis

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