Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor

We have shown previously that the antiviral function of CD4+ T
lymphocytes against murine cytomegalovirus (MCMV) is associated
with the release of interferon- (IFN-). We now demonstrate that
IFN- and tumour necrosis factor alpha (TNF-) display synergism in
their antiviral activity. As little as 2 ng/ml of IFN- and TNF-
reduced the virus yield by about three orders of magnitude. There
was no effect on immediate early (IE) and early (E) gene expression
as far as the candidate genes IE1, E1 and those encoding the major
DNA-binding protein and the DNA polymerase were concerned. Late
gene transcription, assayed by the candidate genes encoding
glycoprotein B and the MCMV homologue of ICP 18.5, was blocked and
MCMV DNA replication was found to be reduced but not halted. The
most prominent finding of the cytokine effect, seen by electron
microscopy, was an alteration of nucleocapsid formation.
Altogether, the synergism is multifaceted and acts at more than one
stage during viral morphogenesis. Because the cytokines clearly do
not act at an early stage of infection we conclude that the mode of
cytokine activity differs between alpha- and betaherpesviruses.