Three newly identified A*24 alleles: A*2406, A*2413 and A*2414

Abstract

Three previously unknown A24-related alleles were identified by PCR-SSO typing and confirmed by DNA sequencing in Australian Aboriginal populations (A*2406, 2413) and in individuals of South American descent (A*2414). A*2406 and A*2413 both have two adjacent (but different) nucleotide substitutions in codon 156 in exon 3 compared to A*2402, resulting in a single amino acid replacement in each allele. The South American A*2414 is apparently a hybrid between A2 and A24 with a segment of the A*24 sequence between codons 95 and 107 in exon 3 replaced with the A*02 sequence. Interallelic sequence exchange is the most likely mechanism in the generation of all three novel alleles. Compared to A*2402, the four amino acid substitutions in the A*2414 molecule would be expected to significantly change the shape of the peptide binding cleft, leading to selection of different peptide ligands. The single amino acid replacements in position 156 of the two Australian Aboriginal A*24 alleles may also have significant functional effects. In particular, Trp replacing Gln in position 156 (A*2406) is predicted to markedly reduce the volume of the peptide binding cleft, influence the interaction of HLA pockets with peptide side chains, and therefore, cause major changes in peptide presentation. These newly defined alleles may reflect the adaptive process of HLA genes to local environments.

Towards identification of immune and genetic correlates of severe influenza disease in Indigenous Australians

“…Our analysis of the LIFT cohort found that Indigenous Australians display a restricted and distinct HLA profile in accordance with previously published serological studies 14 , 15 , 16 . Our molecular HLA typing verified the predominant usage of HLA‐A*02:01, 11:01, 24:02, 34:01 and HLA‐B*13:01, 15:21, 40:01/02, 56:01/02.…”

“…To support the rational design of an effective, broad‐spectrum universal vaccine, it is essential to define the dominant influenza‐specific T‐cell responses focused on the allelic HLA variants characteristic of Indigenous Australians 15 , 16 . Identification of immune and host factors underlying severe influenza disease in Indigenous Australians, highly susceptible to influenza, is of an enormous importance.…”

“…To support the rational design of an effective, broad-spectrum universal vaccine, it is essential to define the dominant influenzaspecific T-cell responses focused on the allelic HLA variants characteristic of Indigenous Australians. 15,16 Identification of immune and host factors underlying severe influenza disease in Indigenous Australians, highly susceptible to influenza, is of an enormous importance. Understanding which individuals within the Indigenous populations (globally) are at risk of developing severe influenza disease (for example, HLA-A24-expressing individuals 12 ) will inform our future prognostic strategies for the treatment and management of severe influenza pneumonia and for designing the vaccination programmes that target specific groups for routine influenza immunisation.…”

“…Indeed, the computational data suggest a strong correlation between pH1N1 influenza‐induced mortality and the expression of HLA‐A24, 12 an allele highly prevalent in Indigenous Australians and Alaskans 13 . Previous studies also suggest that some HLA molecules of Indigenous Australians differ from those that predominate in non‐Indigenous Australians 14 , 15 , 16 . Thus, HLAs expressed in Indigenous populations may bind different viral peptides and induce distinct CD8 + T‐cell responses in comparison with non‐Indigenous individuals.…”

“…13 Previous studies also suggest that some HLA molecules of Indigenous Australians differ from those that predominate in non-Indigenous Australians. [14][15][16] Thus, HLAs expressed in Indigenous populations may bind different viral peptides and induce distinct CD8 + T-cell responses in comparison with non-Indigenous individuals. To date, there are no data on influenza-specific CD8 + T-cell responses, in the context of HLA restriction, in Indigenous Australians.…”