Interferon gamma expressed by a recombinant respiratory syncytial virus attenuates virus replication in mice without compromising immunogenicity

Interferon gamma (IFN-gamma) has pleiotropic biological effects, including intrinsic antiviral activity as well as stimulation and regulation of immun e responses. An infectious recombinant human respiratory syncytial virus (r RSV/mIFN-gamma) was constructed that encodes murine (m) IFN-gamma as a sepa rate gene inserted into the G-F intergenic region. Cultured cells infected with rRSV/mIFN-gamma secreted 22 mu g mIFN-gamma per 10(6) cells. The repli cation of rRSV/mIFN-gamma, but not that of a control chimeric rRSV containi ng the chloramphenicol acetyl transferase (CAT) gene as an additional gene, was 63- and 20-fold lower than that of wild-type (wt) RSV in the upper and lower respiratory tract, respectively, of mice. Thus, the attenuation of r RSV/mIFN-gamma in vivo could be attributed to the activity of mIFN-gamma an d not to the presence of the additional gene per se. The mice mere complete ly resistant to subsequent challenge with wt RSV. Despite its growth restri ction, infection of mice with rRSV/mIFN-gamma induced a level of RSV-specif ic antibodies that, on day 56, was comparable to or greater than that induc ed by infection with wt RSV. Mice infected with rRSV/mIFN-gamma developed a high level of IFN-gamma mRNA and an increased amount of interleukin 12 p40 mRNA in their lungs, whereas other cytokine mRNAs tested were unchanged co mpared with those induced by wt RSV. Because attenuation of RSV typically i s accompanied by a reduction in immunogenicity, expression of IFN-gamma by an rRSV represents a method of attenuation in which immunogenicity can be m aintained rather than be reduced.