Many mammals, including humans, are equipped with genes encoding so-called “restriction factors” that provide considerable resistance to viral infections. To address the role of the interferon-inducible gene IFI16, a member of the HIN-200 gene family, in viral replication, primary human embryo lung fibroblasts (HELFs) containing a knockdown of IFI16 (IFI16-kd) were analyzed for their capacity to support the replication of RNA and DNA viruses. Of the viruses tested, replication of the HCMV AD169 strain, and at a lower degree HSV1 and HSV2, appeared significantly increased compared to that observed in cells expressing non-specific siRNA. Consistent with these results, overexpression of IFI16 inhibited expression of HCMV early genes and down-regulated viral replication. HCMV infection of HELFs induced the up-regulation of IFI16 expression as early as 48 hours post infection, that continued to increase until 96 hours post infection and disappeared thereafter. In addition, HCMV infection was able to modify IFI16 nuclear localization. A confocal double-labeling indirect immunofluorescence assay showed that at 48 h post-infection, IFI16 progressively exited the nucleus and colocalized with HCMV gB in the assembly complex which consists of multivesicular bodies (MVBs). Collectively, our findings indicate for the first time, that the IFI16 protein may function as a restriction factor for HCMV in human cells and unveil the capability of HCMV to evade IFI16 antiviral activity.
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