Differential microRNA regulation of HLA-C expression and its association with HIV control

The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism(1), lower expression on the cell surface(2,3), and more extensive ligand-receptor interactions with killer-cell immunoglobulin-like receptors(4). A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed -35) associates with control of HIV5-7, and with levels of HLA-C messenger RNA transcripts(8) and cell-surface expression(7), but the mechanism underlying its varied expression is unknown. We proposed that the -35 SNP is not the causal variant for differential HLA-C expression, but rather is marking another polymorphism that directly affects levels of HLA-C-7. Here we show that variation within the 3' untranslated region (UTR) of HLA-C regulates binding of the microRNA hsa-miR-148 to its target site, resulting in relatively low surface expression of alleles that bind this microRNA and high expression of HLA-C alleles that escape post-transcriptional regulation. The 3' UTR variant associates strongly with control of HIV, potentially adding to the effects of genetic variation encoding the peptide-binding region of the HLA class I loci. Variation in HLA-C expression adds another layer of diversity to this highly polymorphic locus that must be considered when deciphering the function of these molecules in health and disease.