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Subtypes In Vivo: Intramuscular Injection of IFN Expression Constructs Reduces Cytomegalovirus Replication1
Department of Microbiology, University of Western Australia, Queen Elizabeth II Medical Center, Nedlands, Perth, Western Australia, Australia
The IFN-
cytokines belong to a multigene family. However, the in
vivo biological functions of each of the IFN- subtypes is unknown.
Recently, we developed an experimental model in which the tibialis
anterior muscles of mice were transfected in situ with naked DNA
plasmids encoding an IFN transgene. Here we use this model to
investigate the in vivo effect of the expression of three murine
IFN- subtypes (A1, A4, and
A9) on murine CMV replication in C57BL/6, BALB/c,
and A/J mice. CMV was shown to replicate in the tibialis anterior
muscles of mice for at least 6 days and induced an inflammatory
infiltrate. However, mice expressing the IFN- transgenes showed a
marked reduction in the peak titers of virus replication, with less
severe inflammation in the muscles compared with control mice that were
inoculated with blank vectors. Moreover, mice expressing the IFN-1
transgene had significantly lower CMV titers in the inoculated muscle
than mice expressing either the IFN-4 or the IFN-9 transgenes.
Furthermore, IFN-/ß receptor knockout mice had markedly higher
levels of CMV replication in the tibialis anterior muscles than the
wild-type parental strain (129/Sv/Ev) following IFN-1 transgene
inoculation, suggesting that the protection observed is due to host
cell-mediated IFN signaling. These data provide the first evidence
indicating that there are in vivo differences in the antiviral efficacy
of the IFN- subtypes.
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