Infection of H5N1 influenza virus causes the highest mortality among all influenza viruses.The mechanisms underlying such high viral pathogenicity are incompletely understood.Here,we report that the H5N1 influenza virus encodes a microRNA-like small RNA,miR-HA-3p,which is processed from a stem loop-containing viral RNA precursor by Argonaute 2,and plays a role in enhancing cytokine production during H5N1 infection.Mechanistic study shows that miR-HA-3p targets poly(rC)-binding protein 2 (PCBP2) and suppresses its expression.Consistent with PCBP2 being an important negative regulator of RIG-I/MAVS-mediated antiviral innate immunity,suppression of PCBP2 expression by miR-HA-3p promotes cytokine production in human macrophages and mice infected with H5N1 virus.We conclude that miR-HA-3p is the first identified influenza virus-encoded microRNA-like functional RNA fragment and a novel virulence factor contributing to H5N1-induced'cytokine storm'and mortality.