Interferon Gamma Inhibits Varicella-Zoster Virus Replication in a Cell Line-Dependent Manner

Abstract

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. IMPORTANCE 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.

New insights into IFN-γ in rheumatoid arthritis: role in the era of JAK inhibitors

“…IFN-c-IRF1 axis was more potent than IFN-a-IRF9 axis in blocking VZV infection of primary human fibroblasts [60]. Conversely, in some cell lines (e.g., MeWo melanoma cells), IFN-b, but not IFN-c, exerted an anti-VZV activity [61]. The defensive role of type I IFN against VZV infection is also supported by a clinical trial revealing an increased incidence of herpes zoster with the use of anifrolumab, a human anti-type I IFN receptor monoclonal antibody, for patients with systemic lupus erythematosus [62].…”

“…Given the findings that patients with multiple myeloma, which is associated with humoral immunity defects, present with increased herpes zoster incidence only after treatment with the proteasome inhibitor bortezomib [59], cell-mediated immunity may play a greater role than humoral immunity in the host defense against VZV. Both type I IFN and IFN-c have been shown to act on the cells to restrict VZV replication and spread [60,61]. IFN-c-IRF1 axis was more potent than IFN-a-IRF9 axis in blocking VZV infection of primary human fibroblasts [60].…”

Manipulation of the Innate Immune Response by Varicella Zoster Virus

“…Another recent report indicates there are cell type specific activities in the relative ability of IFNβ and IFNγ to limit virus production. IFNγ could profoundly inhibit VZV production in ARPE-19, A549, MRC-5 but had only very limited capacity to inhibit infection in MeWo cells, where IFNβ retained the capacity to significantly reduce viral yield (120). IFNγ could also promote survival of VZV infected neurons to potentially ensure the efficient establishment of latency (121).…”

The beneficial effects of varicella zoster virus

“…Survivin, which is abundant in cancers and tissues that contain proliferating cells, mediates a necessary virusenhancing effect of STAT3 activation on VZV [426]. The major IE-62 protein of VZV is delivered to the newly infected cell nuclei where it initiates VZV replication [429]. IE-62 protein is the predominant VZ virion tegument protein [427].…”

“…IE-62 protein is the predominant VZ virion tegument protein [427]. It activates the expression of all kinetic classes of VZV genes [427,429]. IFN-γ blocks VZV replication by inhibiting IE-62 function in a cell line-dependent manner [429].…”