Cytomegaloviruses are known to encode several gene products that function to subvert MHC-dependent immune recognition. Here we characterize a rat cytomegalovirus (RCMV) C-type lectin-like (RCTL) gene product with homology to the Clr ligands for the NKR-P1 receptors. RCMV infection rapidly extinguished host Clr-b expression, thereby sensitizing infected cells to killing by natural killer (NK) cells. However, the RCTL protein functioned as a decoy ligand to protect infected cells from NK killing via direct interaction with the NKR-P1B inhibitory receptor. In vivo, an RCTL mutant virus displayed diminished virulence in an NK-dependent and strain-specific manner, suggesting that host NKR-P1 polymorphisms have evolved to avert the viral decoy mechanism while maintaining Clr-b recognition to preserve self tolerance. These findings reveal a unique strategy adopted by cytomegaloviruses to evade MHC-independent self-nonself discrimination. The existence of lectin-like genes in several poxviruses suggests that this may represent a common theme for viral evasion of innate immunity.

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Radiation resistance poses a major clinical challenge in cancer treatment, but little is known about how microRNA (miR) may regulate this phenomenon. In this study, we used next-generation sequencing to perform an unbiased comparison of miR expression in PC3 prostate cancer cells rendered resistant to fractionated radiation treatment. One miR candidate found to be upregulated by ionizing radiation was miR-95, the enforced expression of which promoted radiation resistance in a variety of cancer cells. miR-95 overexpression recapitulated an aggressive phenotype including increased cellular proliferation, deregulated G 2 -M checkpoint following ionizing radiation, and increased invasive potential. Using combined in silico prediction and microarray expression analyses, we identified and validated the sphingolipid phosphatase SGPP1, an antagonist of sphingosine-1-phosphate signaling, as a target of miR-95 that promotes radiation resistance. Consistent with this finding, cell treatment with FTY720, a clinically approved small molecule inhibitor of S1P signaling, sensitized miR-95 overexpressing cells to radiation treatment. In vivo assays extended the significance of these results, showing that miR-95 overexpression increased tumor growth and resistance to radiation treatment in tumor xenografts. Furthermore, reduced tumor necrosis and increased cellular proliferation were seen after radiation treatment of miR-95 overexpressing tumors compared with control tumors. Finally, miR-95 expression was increased in human prostate and breast cancer specimens compared with normal tissue. Together, our work reveals miR-95 expression as a critical determinant of radiation resistance in cancer cells. Cancer Res; 73(23); 6972-86. Ó2013 AACR.