The MHC class I alleles HLA-B*4402 and HLA-B*4405 differ at only one amino acid, yet this difference markedly affects their ability to access alternative pathways of antigen presentation and their susceptibility to viral interference of conventional presentation pathways. Reporting in The Journal of Experimental Medicine, James McCluskey, Jamie Rossjohn and colleagues propose that such naturally occurring HLA polymorphisms might represent an evolutionary trade-off between optimal HLA class I loading and effective pathogen evasion.

Naturally occurring HLA polymorphisms in the peptide-binding groove increase the diversity of epitopes that are presented to T cells. Accordingly, analysis of the peptides eluted from the two HLA-B44 alleles indicated that the single amino-acid change at position 116 (present in the F pocket of the peptide-binding groove), from aspartic acid in HLA-B*4402 to tyrosine in HLA-B*4405, resulted in a preference for phenylalanine at position 9 of the peptide. This was due to decreased electronegativity and increased hydrophobicity of the F pocket of HLA-B*4405.

In addition to an influence on peptide-binding specificity, polymorphism at position 116 has been shown to affect allele dependency on the peptide-loading complex (PLC) for optimal peptide loading and cell-surface expression. HLA-B*4402 cell-surface expression is highly dependent on tapasin, which recruits HLA class I molecules into the PLC. By contrast, HLA-B*4405 was shown to be expressed at high levels on the surface of tapasin-deficient cells and without association with the PLC. Furthermore, compared with HLA-B*4402, HLA-B*4405 was more rapidly transported to the surface of both tapasin-deficient and tapasin-sufficient cells by circumventing PLC-mediated retention and peptide optimization in the endoplasmic reticulum (ER).

Given the ability of HLA-B*4405 to efficiently bind peptides independent of the PLC, the authors asked whether this provided resistance to TAP (transporter for antigen processing) blockade by the herpes simplex virus (HSV)-encoded TAP inhibitor ICP47. The expression of HLA-B*4402 was markedly reduced in the presence of ICP47 due to impaired peptide delivery to the ER; however, the expression of HLA-B*4405 was only marginally reduced, indicating that it can rapidly capture peptide even when in limited supply. The resistance of HLA-B*4405 to viral interference of the PLC was also confirmed using peripheral-blood mononuclear cells infected with HSV.

So, although sacrificing the optimization of peptide cargo by the PLC can come at a cost to the host, tapasin-independent alleles such as HLA-B*4405 might have been selected to provide an advantage during infection with pathogens that interfere with conventional antigen-presentation pathways.