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Effector Functions and Regulation of Host Antiviral Immunity


Interferons (IFNs) are essential anti-viral cytokines that suppress viral infections by upregulation of antiviral effectors, collectively called interferon-stimulated genes (ISGs). We identified ISGs by gene expression profiling and performed functional screen of 288 ISGs that have antiviral activity against vesicular stomatitis virus (VSV) and murine gammaherpes virus (MHV68). Validation of antiviral genes from the screen demonstrated ISGs have inhibitory effect on specific virus. In particular, BMP2 inhibited MHV68 but not VSV replication. Conversely, Tap1 overexpression and deficiency led to resistance and susceptibility to VSV infection, respectively, while having effect on MHV68 growth.

Initially identified by its antiviral activity against VSV and MHV68, cholesterol-25-hydroxylase (Ch25h) was found to be an ISG that cause antiviral effect by production of a soluble oxysterol, 25-hydroxycholesterol. Toll-like receptor agonists induced Ch25h in an IFN-dependent manner. Ch25h overexpression and 25HC treatment broadly inhibited replication of other enveloped RNA and DNA viruses, including HIV, HSV, RSSEV, RVFV, and EBOV. Ch25h and 25HC inhibited efficiency of viral fusion in VSV and HIV. Administration of 25HC suppresses HIV replication in humanized mice, while functional loss of Ch25h lead to increased susceptibility to infections in vitro and in vivo.

Since interferons regulate many genes that can have profound impact on cellular homeostasis, regulation of IFN is tightly regulated. We have identified retinoid-X-receptors (RXR) to be a suppressor of type-I IFN response. Overexpression of RXR and activation of RXR with RXR-specific agonists led to increased viral susceptibility to viral infection in RAW264.7 cell lines. Functional loss of RXR in F9 embryonal caricoma cell lines led to increased resistance to viral infection. RXR agonists inhibited phosphorylation of upstream signaling activators of IFN, TBK and IRF3. Gene expression analyses show RXR inhibited many ISGs induced by dsRNA mimetic, polyI:C and partial suppression of genes induced by lipidA.

In effort to use virus as a tool to improve immunity, we developed an approach for live-attenuated vaccine development by genome-wide profiling. Using flu as a model, we generated high-density mutations in the influenza (WSN strain) M-gene and profiled the fitness of every mutation in vivo through time. By selecting mutants that exhibited an attenuated growth profile, we identified a mutant, W7-791, that grew in vitro, infected mice, and was not virulent. Vaccination of mice with W7-791 conferred protection against lethal infectious dose of two strains of H1N1 influenza and a phylogenetically disparate, H3N2 virus.

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