Combined sequential treatment with interferon and dsRNA abrogates virus resistance to interferon action

Many viruses have evolved mechanisms to resist the action of interferon (IF N), These include production of viral gene products that sequester double-s tranded RNA (dsRNA) and of small helical RNA. These potentially prevent act ivation of dsRNA-dependent pathways of IFN action or block expression of ce llular genes activated exclusively by dsRNA that may contribute to the anti viral state. Thus, dsRNA might be rate limiting in the development of an IF N-mediated antiviral state. In support of this hypothesis, dsRNA added exog enously to IFN-treated cells in the form of poly(rI):poly(rC) is shown to e stablish in a dose-dependent manner an antiviral state against two viruses otherwise highly refractory to IFN action, avian reovirus (ARV) and Newcast e disease virus (NDV), Cells exposed singly to high doses of IFN or dsRNA r educed the plaque-forming capacity of these viruses on chicken embryo cells 2-fold. When used in combination, there was up to a 100-fold reduction. In order to abrogate IFN resistance, dsRNA must be added after, not before, a n IFN-mediated latent antiviral state is established. dsRNA added exogenous ly is thought to achieve the threshold required for activation of dsRNA-dep endent pathways of IFN action or to induce some dsRNA-stimulated gene whose product acts synergistically with that of some IFN-stimulated gene. The co mbined sequential treatment with IFN and dsRNA may be useful in overcoming the anti-IFN activity of viruses of clinical interest or in other clinical conditions.