Graphic by M. Miner
For unknown reasons, the pandemic A/H1N1 influenza virus (pH1N1) is more deadly in indigenous populations around the world than those of European/Caucasian descent. While many factors impact the severity of influenza disease (e.g., obesity, socioeconomic status, age), potential genetic components for this disparity are not completely known. One such component is a person’s human leukocyte antigen (HLA): HLA molecules bind pathogen antigens and then the HLA-antigen complex is recognized by the person’s T cells. Our immune response to viruses can depend heavily on HLA types/alleles, which are very diverse, and therefore differences in one’s HLA alleles can drastically affect T-cell responses and disease outcome.
VIDD scientists wondered whether people who are more susceptible to pH1N1 have a similar HLA genotype that differs from less-susceptible populations. This study, led by VIDD Staff Scientist Dr. Tomer Hertz and included Members Dr. Betz Halloran and Dr. Larry Corey, used a computational tool called ‘targeting efficiency’ as a way to measure if a certain HLA preferentially binds conserved or variable regions of viral proteins. Binding conserved viral antigens (high targeting efficiency) results in a more robust and successful immune response than binding variable regions (low targeting efficiency).
Hertz, et al. computed the HLA targeting efficiency scores for the 95 most prevalent HLA class-I alleles against pH1N1 and several other influenza subtypes. The authors found that HLA A*24 alleles had the lowest efficiency scores toward multiple influenza strains, including the 1918 pandemic strain, suggesting that HLA A*24 alleles may be an associated risk factor for reduced clearance and hence increased severity of H1N1 influenza infections. To assess the clinical impact of these predictions, VIDD scientists collaborated with Dr. Paul Thomas from St. Jude Children’s Research Hospital, who performed a clinical trial on individuals infected during the 2009 pandemic. Using samples obtained from that cohort, they measured IFNγ (an antiviral molecule) production from T cells stimulated with pH1N1 antigen. The authors found that participants’ HLA targeting efficiency scores significantly correlated with IFNγ production. Interestingly, HLA A*24 is a highly prevalent allele in many indigenous populations. This study provides a potential, partial biological explanation for the higher rates of H1N1-related mortality seen in indigenous populations, and provides a foundation for the implementation of surveillance programs for populations with high risk of influenza morbidity.