Antiviral andProtein-Inducing Activities ofRecombinant Human Leukocyte Interferons andTheirHybrids

virus were studied infeline, human,andmurinecells. Although theseinterferon species hadwidely different potencies, their activities against these viruses were,ingeneral, proportional. TheIFN-aA/D(Bgl) hybrid was themostpotentspecies, andtheIFN-aD/A(Bgl) hybrid was theleast potent. However, thelatter species didnotinterfere withtheaction oftheformerspecies. Likenatural humanleukocyte interferon, eachofthesevenspecies ofrecombinant interferons induced thesynthesis ofatleast five proteins inhuman fibroblasts, whereas induction ofonlyone suchprotein was readily detected ina feline fibroblast linein whichthese interferon species inhibited thereplication ofallthree viruses. Humanleukocyte interferon (IFN-a) consists ofmany species that areencoded byindividual membersoftheIFNaxmultigene family. Someofthesespecies havebeenexpressed inbacteria. Extensive sequence homologies among theIFN-ageneshavepermitted theconstruction ofhybrid recombinant molecules (reviewed inreference 6). Although interferon action wasoriginally considered tobe species specific, this concept hasbeenmodified substantially.SomehumanIFN-aspecies exhibit high levels ofactivity onnonhuman cells. Insomecases, their potency ishigher in heterologous cells thaninhumancells. IFN-aAandIFN-aD exhibit quantitatively different activities oncells fromdifferentorganisms, andthehybrids ofthese twoIFN-aspecies havetheir owncharacteristic spectra ofactivity thatare distinct fromthose oftheparental molecules (7,9,13,14). Thebiological action oftheleukocyte interferon species andtheir hybrids hasbeentested predominantly bymeasuringtheir antiviral activity against vesicular stomatitis virus (VSV). Since different molecular mechanisms areinvolved ininterferon mediated inhibition ofreplication ofdifferent viruses (reviewed inreferences 4and10), itisnotknown whether theconclusions drawnabout thespecies specificity andthereceptor interactions fromthese measurements with VSV wouldalsobetrueforactions ofinterferon against otherviruses. Forexample, theantiretroviral action of interferon isexerted atthelevel ofviral assembly and release fromtheplasma membrane, whereas replication of exogenously infecting cytopathic viruses suchasVSV or encephalomyocarditis virus (EMCV)isinhibited atthelevel ofviral RNA andprotein synthesis. Celllines havebeen described inwhichinterferon doesnotinhibit EMCV or VSVbutinhibits theproduction ofretroviruses (2,3,11). It hasalso beenreported that incertain cell lines interferon can inhibit VSVwithout inhibiting EMCV,orviceversa (5,11), indicating thatthesetwoviruses areinhibited bydifferent mechanisms. Itisnotclear atwhichpoints ofinterferon action thedifferential antiviral pathways diverge fromone another.