The Antiviral Efficacy of the Murine Alpha-1 Interferon Transgene against Ocular Herpes Simplex Virus Type 1 Requires the Presence of CD4 + , α/β T-Cell Receptor-Positive T Lymphocytes with the Capacity To Produce Gamma Interferon

Abstract

ABSTRACT Alpha/beta interferons (IFN-α/βs) are known to antagonize herpes simplex virus type 1 (HSV-1) infection by directly blocking viral replication and promoting additional innate and adaptive, antiviral immune responses. To further define the relationship between the adaptive immune response and IFN-α/β, the protective effect induced following the topical application of plasmid DNA containing the murine IFN-α1 transgene onto the corneas of wild-type and T-cell-deficient mice was evaluated. Mice homozygous for both the T-cell receptor (TCR) β- and δ-targeted mutations expressing no αβ or γδ TCR (αβ/γδ TCR double knockout [dKO]) treated with the IFN-α1 transgene succumbed to ocular HSV-1 infection at a rate similar to that of αβ/γδ TCR dKO mice treated with the plasmid vector DNA. Conversely, mice with targeted disruption of the TCR δ chain and expressing no γδ TCR + cells treated with the IFN-α1 transgene survived the infection to a greater extent than the plasmid vector-treated counterpart and at a level similar to that of wild-type controls treated with the IFN-α1 transgene. By comparison, mice with targeted disruption of the TCR β chain and expressing no αβ TCR + cells (αβ TCR knockout [KO]) showed no difference upon treatment with the IFN-α1 transgene or the plasmid vector control, with 0% survival following HSV-1 infection. Adoptively transferring CD4 + but not CD8 + T cells from wild-type but not IFN-γ-deficient mice reestablished the antiviral efficacy of the IFN-α1 transgene in αβ TCR KO mice. Collectively, the results indicate that the protective effect mediated by topical application of a plasmid construct containing the murine IFN-α1 transgene requires the presence of CD4 + T cells capable of IFN-γ synthesis.