The interferon system. (1) To explore further our recent discovery that defective interfering particles of vesicular stomatitis virus (VSV) which contain covalently linked message and anti-message do not kill cells, but are exquisitely efficient inducers of interferon. We plan to define the role of these interferon-inducing (plus or minus) RNA DI particles in persistent infection by VSV, and determine how ubiquitous is their distribution. (2) To determine why primary cells aged in vitro hyperproduce interferon and develop an enhanced antiviral state upon stimulation with appropriate inducers. (3) To examine in depth our recent discovery that poly (rI) - poly (rC) induces a double-stranded RNase in avian, but apparently not in mammalian cells. We plan to ascertain the extent to which dsRNA-induced dsRNase contributes to an antiviral state. (4) To define the significance of interferon action in the inhibition of primary transcription in cells infected ith VSV. (5) To use temperature-sensitive (ts) mutants of VSV, Sindbis and NDV, selective inhibitors of macromolecular synthesis, and viral interference per se as probes to determine the role of cellular and viral factors in cell-killing by viruses, subviral components, and dsRNA of viral and synthetic origin. (6) To test further our hypothesis that cell-killing by VSV requires functional virion-associated transcriptase (not new-transcriptase) to synthesize mRNAs for proteins N and NS and that they be translated into minimally functional proteins. (7) To define the role of the interferon system in the prevention of cell-killing by viruses. BIBLIOGRAPHIC REFERENCES: Defective Interfering Particles with Covalently Linked (positive and negative) RNA Induce Interferon Philip I. Marcus and Margaret J. Sekellick, Nature, 1977, in press. Cell Killing by Viruses IV. Cell Killing and Protein Synthesis Inhibition by Vesicular Stomatitis Virus Require the same Gene Functions J.L. Marvaldi, J. Lucas-Lenard, M.J. Sekellick and P.I. Marcus, Virology, 1977, in press.