A new study published in Science shows that a microRNA (miRNA) encoded by human cytomegalovirus (HCMV) targets the MHC-class-I-polypeptide-related sequence B (MICB) gene, downregulating its expression during viral infection and reducing natural killer (NK)-cell-mediated killing.

miRNAs comprise an extensive class of evolutionarily conserved noncoding RNAs of approximately 22 nucleotides in length that regulate post-transcriptional gene expression. In most cases, miRNAs reduce the abundance or translational efficiency of target mRNAs, although the mechanism by which this is achieved is not fully understood. Recent reports of virally encoded miRNAs in herpesviruses, however, suggest that miRNAs may have other functions.

In this study, the authors considered the possible role of virally encoded miRNAs in immune evasion by HCMV, which has effective immune evasion strategies. HCMV encodes many immunomodulatory proteins that manipulate the immune response, as well as at least 11 miRNAs. Using a newly developed algorithm for predicting miRNA targets, Stern-Ginossar et al. searched for potential binding sites of the 11 known HCMV miRNAs. MICB was the top predicted target of one particular miRNA, hcmv-miR-UL112. MICB (as well as MICA) is a ligand for the NK-cell receptor NKG2D (natural-killer group 2, member D), and its expression is induced by cellular stress caused by, for example, viral infection. The expression of MICB on the cell surface marks that cell for killing by NK cells. Cell-surface expression of MICB is specifically downregulated by the UL16 protein of HCMV.

To assess the function of hcmv-miR-UL112, the authors expressed this miRNA in human tumour cell lines that endogenously express MICA and MICB and observed a specific and extensive downregulation of MICB. Further, by using a mutated HCMV virus the authors showed that hcmv-miR-UL112 specifically downregulates MICB expression during viral infection, leading to decreased binding of NKG2D and reduced killing by NK cells.

So, in addition to its UL16-protein-based strategy, HCMV also uses an miRNA-based strategy to evade the host immune response, by downregulating one of the molecules that NK cells use to recognize virus-infected cells. The authors note that the potential therapeutic applications of this new mechanism could include antiviral therapy by targeting these viral miRNAs, and immunosuppressive therapy by mimicking their roles.