Synergy of type I interferon‐A6 and interferon‐B naked DNA immunotherapy for cytomegalovirus infection

Abstract

Summary Delivery of type I IFN transgenes by naked DNA immunization can protect against cytomegalovirus infection and myocarditis. Here, we investigate IFN transgene expression, antiviral efficacy, and immunomodulation of myocarditis using various treatment regimes in a mouse CMV model. In vivo expression of the IFN transgene was observed in the sera for 35 days post-DNA inoculation. Prophylactic IFN-A6 and IFN-B DNA treatment for 14 days prior to murine cytomegalovirus (MCMV) infection was more efficacious in significantly reducing viral titres, than 2 days prior to or 2 days post-virus infection. Similarly, IFN-A6 DNA treatment commencing 14 days prior to virus infection was superior in suppressing both acute and chronic myocarditis. Furthermore, reduction of autoantibody titres was more pronounced when IFN was administered 14 days prior to viral infection. Combinational IFN gene therapy was assessed for synergy between IFN subtypes. Combination treatment with either IFN-A6/A9 or IFN-A6/B greatly reduced spleen viral titres while IFN-A6/B and IFN-A9/B reduced virus replication in the liver. Only IFN-A6/A9 and IFN-A9/B reduced acute viral myocarditis, whereas IFNA6/B treatment was most efficacious for autoimmune chronic myocarditis. Finally, treatment with IFN-A6 DNA 2 weeks post-MCMV infection proved effective at inhibiting the development of chronic autoimmune myocarditis. These findings suggest that immunomodulation of both antiviral and autoimmune responses by IFN DNA immunization may be an avenue for improved viral immunotherapy.

Type I interferon differential therapy for erythroleukemia: specificity of STAT activation

“…The divergent antiviral effects of the IFN subtypes are evident against numerous viruses including murine cytomegalovirus, 51,58 herpes simplex virus type 1 (HSV-1), 59 and HSV-2. 60 Furthermore, covaccination of IFN subtypes with viral vaccines produces differential protective effects on viral infection.…”

“…The recent establishment, in this laboratory, of a large panel of murine IFN-␣ subtypes and IFN-␤ for DNA gene therapy 51 and IFN protein production 51,58 has provided an avenue through which to explore the anticancer effects of this multigene cytokine family. The divergent antiviral effects of the IFN subtypes are evident against numerous viruses including murine cytomegalovirus, 51,58 herpes simplex virus type 1 (HSV-1), 59 and HSV-2.…”

“…IFN DNA therapy has clearly demonstrated that type I IFNs differ in their antiviral capacity and modulation of the immune response. 51,[57][58][59]93 Other investigators have found that type I IFN is a clinical target with promising antileukemic potential. In cancer treatment, IFN-␣ electroporation gene therapy results in tumor regression.…”

“…13,97 In this study, J2E cell-induced erythroleukemia responded differentially to type I IFN gene therapy, with IFN-A6 and IFN-A9 most effective in prolonging animal survival (P Յ .1) despite similar low levels of all IFN DNA transgenes expressed in vivo (10-40 IU/mL). 51,58 Thus IFN subtype transgene expression in mice is biologically effective using the naked DNA delivery system. Indeed research by Piehler et al 98 suggested that "for maintaining transcription of IFN-responsive genes over a longer time period, low but continuous signaling through the IFN receptor is essential."…”

Interferons: Mechanisms, Biological Activities and Survey of their Use in Human Diseases

“…Recent studies suggest that immunomodulation of both antiviral, antitumor and autoimmune responses by IFN DNA immunization may be an avenue for improved immunotherapy [9,29]. For example, delivery of type I IFN transgenes by naked DNA immunization can protect against cytomegalovirus infection and myocarditis [9,39,40,83]. The development of IFN-based gene therapy is currently being tested to stimulate the immune system of patients with various viral or tumor diseases [29,56,83].…”