RNASE-L MEDIATES THE ANTIVIRAL EFFECT OF INTERFERON THROUGH A SELECTIVE REDUCTION IN VIRAL-RNA DURING ENCEPHALOMYOCARDITIS VIRUS-INFECTION

The 2',5'-oligoadenylate (2-5A) system is an RNA degradation pathway w hich plays an important role in the antipicornavirus effects of interf eron (IFN), RNase L, the terminal component of the 2-5A system, is tho ught to mediate this antiviral activity through the degradation of vir al RNA; how el er, the capacity of RNase L to selectively target viral RNA has not been carefully examined in intact cells, Therefore, the m echanism of RNase L-mediated antiviral activity was investigated follo wing encephalomyocarditis virus (EMCV) infection of cell lines in whic h expression of transfected RNase L was induced or endogenous RNase L activity was inhibited, RNase L induction markedly enhanced the anti-E MCV: activity of IFN via a reduction in EMCV RNA, Inhibition of endoge nous RNase L activity; inhibited this reduction in viral RNA, RNase L had no effect on IFN-mediated protection from vesicular stomatitis, vi rus. RNase L induction reduced the rate of EMCV RN,I synthesis, sugges ting that RNase L may target viral RNAs involved in replication early in the virus life cycle. The RNase L-mediated reduction in viral RNA o ccurred in the absence of detectable effects on specific cellular mRNA s and without any global alteration in the cellular RNA profile, Exten sive rRNA cleavage, indicative of high levels of 2-5A, was not observe d in RNase L-induced, EMCV-infected cells; however, transfection of 2- 5A into cells resulted in widespread degradation of cellular RNAs, The se findings proc ide the first demonstration of the selective capacity of RNase L in intact cells and link this selective activity to cellul ar levels of 2-5A.