Inhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase

TLDR

Interferons trigger antiviral responses, and IFN‑γ suppresses replication of ectromelia, vaccinia, and HSV‑1 in macrophages through nitric oxide production. Inhibition of nitric oxide synthase restores viral replication in IFN‑γ‑treated macrophages, while NO production—via inducible synthase transfection or NO‑generating compounds—restricts replication in epithelial cells and converts resolving ectromelia infection into fulminant disease, demonstrating that NO synthase induction is both necessary and sufficient for IFN‑γ’s antiviral effect.

Abstract

Interferons (IFNs) induce antiviral activity in many cell types. The ability of IFN-γ to inhibit replication of ectromelia, vaccinia, and herpes simplex-1 viruses in mouse macrophages correlated with the cells' production of nitric oxide (NO). Viral replication was restored in IFN-γ-treated macrophages exposed to inhibitors of NO synthase. Conversely, epithelial cells with no detectable NO synthesis restricted viral replication when transfected with a complementary DNA encoding inducible NO synthase or treated with organic compounds that generate NO. In mice, an inhibitor of NO synthase converted resolving ectromelia virus infection into fulminant mousepox. Thus, induction of NO synthase can be necessary and sufficient for a substantial antiviral effect of IFN-γ.