| Cytokines induced by virus infection can play an important role in pathogenesis, virus tropism and spread, and host immunity. Simian virus 5 (SV5) is unusual among paramyxoviruses since infection of epithelial cells results in minimal cytopathic effect and a poor activation of interferon (IFN) pathways. Gene microarray and timecourse experiments indicated that WT rSV5 was also a very poor inducer of proinflammatory cytokines, with the notable exception of moderate induction of RANTES at later times post-infection. By contrast, an engineered P/V mutant (rSV5-P/V-CPI-) and a naturally-occurring variant WF-PIV (Wake Forest - Parainfluenza Virus) were both potent activators of a number of cytokines, including IL-8, IL-6, and RANTES. The mechanism of RANTES induction by the two SV5 variants shared common properties, since RANTES secretion from infected cells had similar kinetics, depended on virus replication, correlated with increased RANTES promoter activation, and was reduced by inhibitors of MAPK and PI3K pathways. Based on previous work on rSV5-P/V-CPI-, we tested the hypothesis that the two SV5 variants activated cytokine secretion due to P/V mutations that accelerated gene expression. Surprisingly, in contrast to the accelerated viral gene expression of rSV5-P/V-CPI-, WF-PIV infection showed a delay in viral replication and infected cells did not show high level viral RNA and protein expression until ∼12--24 h pi. Sequence analysis of the WF-PIV 3' end genes revealed a number of mutations compared to WT rSV5. Chimeric viruses harboring the WF-PIV P/V or M genes in the context of the other rSV5 genes had growth properties similar to WT rSV5 but induced RANTES secretion to levels higher than that seen with WT rSV5, indicating a role for the WF-PIV P/V and M genes in RANTES induction. Furthermore, a cell line stably expressing WT SV5 V protein secreted reduced levels of RANTES following infection with rSV5-P/V-CPI-, but not following infection with WF-PIV. These data support a model in which the two SV5 variants have distinct molecular bases for the induction of cytokines---rSV5-P/V-CPI---is defective in V protein function while WF-PIV produces an inducer not normally seen during WT rSV5 infection. |
