LATE-PHASE INHIBITION OF MURINE CYTOMEGALOVIRUS REPLICATION BY SYNERGISTIC ACTION OF INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR

We have shown previously that the antiviral function of CD4(+) T lymph ocytes against murine cytomegalovirus (MCMV) is associated with the re lease of interferon-gamma (IFN-gamma). We now demonstrate that IFN-gam ma and tumour necrosis factor alpha (TNF-a) display synergism in their antiviral activity. As little as 2 ng/ml of IFN-gamma and TNF-alpha r educed the virus yield by about three orders of magnitude. There was n o effect on immediate early (IE) and early (E) gene expression as far as the candidate genes IE1, E1 and those encoding the major DNA-bindin g protein and the DNA polymerase were concerned. Late gene transcripti on, assayed by the candidate genes encoding glycoprotein B and the MCM V homologue of ICP 18.5, was blocked and MCMV DNA replication was foun d to be reduced but not halted. The most prominent finding of the cyto kine effect, seen by electron microscopy, was an alteration of nucleoc apsid 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 th e mode of cytokine activity differs between alpha- and betaherpesvirus es.