The major immediate early 62 (IE62) protein of varicella-zoster virus (VZV) is delivered to newly infected cell nuclei， where it initiates VZV replication by transactivating viral immediate early (IE)， early (E)， and late (L) genes. Interferon gamma (IFN-γ) is a potent cytokine produced following primary VZV infection. Furthermore， VZV reactivation correlates with a decline in IFN-γ-producing immune cells. Our results showed that treatment with 20?ng/ml of IFN-γ completely reduced intracellular VZV yield in A549 lung epithelial cells， MRC-5 lung fibroblasts， and ARPE-19 retinal epithelial cells at 4?days post-VZV infection. However， IFN-γ reduced virus yield only 2-fold in MeWo melanoma cells ... More
The major immediate early 62 (IE62) protein of varicella-zoster virus (VZV) is delivered to newly infected cell nuclei， where it initiates VZV replication by transactivating viral immediate early (IE)， early (E)， and late (L) genes. Interferon gamma (IFN-γ) is a potent cytokine produced following primary VZV infection. Furthermore， VZV reactivation correlates with a decline in IFN-γ-producing immune cells. Our results showed that treatment with 20?ng/ml of IFN-γ completely reduced intracellular VZV yield in A549 lung epithelial cells， MRC-5 lung fibroblasts， and ARPE-19 retinal epithelial cells at 4?days post-VZV infection. However， IFN-γ reduced virus yield only 2-fold in MeWo melanoma cells compared to that of untreated cells. IFN-β significantly inhibited VZV replication in both ARPE-19 and MeWo cells. In luciferase assays with VZV open reading frame 61 (ORF61) promoter reporter plasmid， IFN-γ abrogated the transactivation activity of IE62 by 95%， 97%， and 89% in A549， ARPE-19， and MRC-5 cells， respectively. However， IFN-γ abrogated IE62's transactivation activity by 16% in MeWo cells， indicating that IFN-γ inhibits VZV replication as well as IE62-mediated transactivation in a cell line-dependent manner. The expression of VZV IE62 and ORF63 suppressed by IFN-γ was restored by JAK1 inhibitor treatment， indicating that the inhibition of VZV replication is mediated by JAK/STAT1 signaling. In the presence of IFN-γ， knockdown of interferon response factor 1 (IRF1) increased VZV replication. Ectopic expression of IRF1 reduced VZV yields 4，000-fold in MRC-5 and ARPE-19 cells but 3-fold in MeWo cells. These results suggest that IFN-γ blocks VZV replication by inhibiting IE62 function in a cell line-dependent manner. Our results showed that IFN-γ significantly inhibited VZV replication in a cell line-dependent manner. IFN-γ inhibited VZV gene expression after the immediate early stage of infection and abrogated IE62-mediated transactivation. These results suggest that IFN-γ blocks VZV replication by inhibiting IE62 function in a cell line-dependent manner. Understanding the mechanisms by which IFN-γ plays a role in VZV gene programming may be important in determining the tissue restriction of VZV.
