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

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Abstract
Variation in cell-surface levels and expression of the major histocompatibility complex component HLA-C have been implicated in the control of HIV viral load and progression to AIDS. The microRNA miR-148a is now shown to regulate the expression of HLA-C expression and its effects on HIV. The discovery of a role for a microRNA in this process raises the possibility of new approaches to immunotherapy. The HLA-C locus is distinct relative to the other classical HLA class I loci in that it has relatively limited polymorphism1, lower expression on the cell surface2,3, and more extensive ligand–receptor interactions with killer-cell immunoglobulin-like receptors4. A single nucleotide polymorphism (SNP) 35 kb upstream of HLA-C (rs9264942; termed −35) associates with control of HIV5,6,7, and with levels of HLA-C messenger RNA transcripts8 and cell-surface expression7, 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-C7. 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.