http://www.nature.com/ncb/journal/v12/n5/abs/ncb2054.html?lang=en Nature Cell Biology 12, 513 - 519 (2010) Published online: 25 April 2010 | doi:10.1038/ncb2054 miR-132 regulates antiviral innate immunity through suppression of the p300 transcriptional co-activator Dimitrios Lagos1, Gabriel Pollara1, Stephen Henderson1, Fiona Gratrix1, Martin Fabani2, Richard S.B. Milne3, Frances Gotch4 & Chris Boshoff1 MicroRNAs are small, non-coding RNAs that negatively regulate gene expression1. It has been proposed that microRNAs could function in the regulation of innate immunity2, 3, but this has not been demonstrated for viral infection. Here we test this hypothesis using the human pathogenic virus Kaposi's sarcoma-associated herpesvirus (KSHV) and one of its putative natural cellular targets, primary lymphatic endothelial cells4 (LECs). We show that an early antiviral microRNA response (6 h post-infection) includes expression of microRNAs that enhance viral gene expression. In particular, the CREB-induced miR-132 microRNA is highly upregulated after infection and has a negative effect on the expression of interferon-stimulated genes, facilitating viral replication. We show a similar function for miR-132 during infection of monocytes with herpes simplex virus-1 (HSV-1) and human cytomegalovirus (HCMV). miR-132 regulates innate antiviral immunity by inhibiting expression of the p300 transcriptional co-activator. p300 is downregulated early after KSHV infection, and inhibition of miR-132 induction restores p300 expression. Furthermore, p300 regulates miR-132 levels, revealing a dynamic equilibrium between miR-132 and p300. By targeting p300, rather than a transcription factor or signalling protein, miR-132 has a broad role in the regulation of antiviral immunity.