MicroRNA regulation of IFN-β protein expression: Rapid and sensitive modulation of the innate immune response

IFN-β production is an inaugural event in the innate immune response to viral infections, with relatively small fold changes in IFN-β expression resulting in the activation ofimportant antiviral signaling cascades. In our rapid SIV/macaquemodel ofHIVencephalitis, the virus enters the CNS within 4 d of infection, accompanied by a marked IFN-β response that wanes as SIV replication is controlled. The centrality of IFN-β to the innate antiviral response in the CNS combines with the potential inflammatory damage associated with long-term activation of this pathway to suggest that IFN-β may be subject to regulatory fine-tuning in addition to well-established transcriptional and message stability mechanisms of regulation. In this paper, we present for the first time evidence that microRNAs (miRNAs), including miR-26a, -34a, -145, and let-7b, may directly regulate IFN-β in human and macaque cells. In primary primate macrophages, the main cell type implicated in HIV and SIV infection in the CNS, specific miRNAs reduce, whereas miRNA inhibitors enhance, IFN-β protein production. The potential biologic significance of this regulation is supported by evidence of an apparent negative feedback loop, with increased expression of three IFN-β-regulating miRNAs by primatemacrophages exposed to recombinant IFN-β or stimulated to produce IFN-β. Thus, miRNAs may contribute significantly to the regulation of IFN-β in innate immune responses.