The antiviral efficacy of the murine alpha-1 interferon transgene against ocular herpes simplex virus type 1 requires the presence of CD4(+), alpha/beta T-cell receptor-positive T lymphocytes with the capacity to produce gamma interferon.
Alpha/beta interferons (IFN-alpha/betas) 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-alpha/beta, the protective effect induced following the topical application of plasmid DNA containing the murine IFN-alpha 1 transgene onto the corneas of wild-type and T-cell-deficient mice was evaluated. Mice homozygous for both the T-cell receptor (TCR) beta- and delta-targeted mutations expressing no alpha beta or gamma delta TCR (alpha beta/gamma delta TCR double knockout [dKO]) treated with the IFN-alpha 1 transgene succumbed to ocular HSV-1 infection at a rate similar to that of alpha beta/gamma delta TCR dKO mice treated with the plasmid vector DNA. Conversely, mice with targeted disruption of the TCR delta chain and expressing no gamma delta TCR(+) cells treated with the IFN-alpha 1 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-alpha 1 transgene. By comparison, mice with targeted disruption of the TCR beta chain and expressing no alpha beta TCR(+) cells (alpha beta TCR knockout [KO]) showed no difference upon treatment with the IFN-alpha1 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-gamma-deficient mice reestablished the antiviral efficacy of the IFN-alpha 1 transgene in alpha beta TCR KO mice. Collectively, the results indicate that the protective effect mediated by topical application of a plasmid construct containing the murine IFN-alpha 1 transgene requires the presence of CD4(+) T cells capable of IFN-gamma synthesis.
Carr
Daniel J J
DJ
Department of Ophthalmology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA. dan-carr@ouhsc.edu
Noisakran
Sansanee
S
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002522:Chlorocebus aethiops; D015316:Genetic Therapy / Q000379:methods; D018259:Herpesvirus 1, Human / Q000502:physiology*; D016898:Interferon-alpha / Q000235:genetics* / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D051379:Mice; D010957:Plasmids / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013666:Tears / Q000821:virology; D019076:Transgenes; D014709:Vero Cells; D014779:Virus Replication
D016898:Interferon-alpha; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma