Molecular Pharmacology, Vol 13, 585-597, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Mechanism of Polyribonucleotide Inhibition of Ribonucleic Acid Tumor Virus Replication: Effect of Poly(inosinic acid) on the Synthesis of Proviral Deoxyribonucleic Acid of Murine Leukemia Virus

¹ Department of Medical Viral Oncology, Roswell Park Memorial Institute, and Graduate Faculty in Microbiology, State University of New York at Buffalo, Roswell Park Division, Buffalo, New York 14263

Single-stranded polyribonucleotides inhibit the replication of RNA tumor viruses in cultured cells with little or no effect on their growth rates or viability. They also inhibit the virion-associated RNA-directed DNA polymerase in vitro. The several polyribonucleotides investigated exhibit a reasonably good correlation between their effects on virus replication in cell culture and on virion-associated RNA-directed DNA polymerase in vitro. These observations suggested that the inhibition of virus replication by polyribonucleotides may be related to their effect on intracellular viral RNA-directed DNA synthesis. Several other observations also indirectly support this notion. For example, polyribonucleotides are more effective when added prior to or just after virus infection; this suggests that an early step in virus infection is affected. The present study concerns the effect of poly(inosinic acid) on viral as well as cellular DNA synthesis in cultured JLS-V9 cells infected with murine leukemia virus. Poly(I) inhibits the synthesis of proviral DNA with little or no effect on cellular DNA synthesis. Furthermore, poly(I), at a concentration inhibitory for proviral DNA synthesis, apparently does not interfere with the uptake of labeled murine leukemia virus by cultured JLS-V9 cells. The effects of poly(I) on partially purified murine leukemia virus and JLS-V9 cell DNA polymerases in vitro were compared. Analysis of the kinetics of inhibition shows that the apparent inhibitory potency of poly(I) toward viral DNA polymerase is 10-50 times that for cellular DNA polymerases. These results support the hypothesis that the inhibition of RNA tumor virus replication by polyribonucleotides is due, at least in part, to their inhibition of proviral DNA synthesis. This is more likely to be due to their effect on viral RNA-directed DNA synthesis than on DNA-directed DNA synthesis.

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ACKNOWLEDGMENTS The author thanks Mr. R. Chawda, Ms. L. Job, and Mr. A. Cairo for technical assistance. The author also thanks Dr. B. I. Milavetz for providing a partially purified preparation of murine leukemia virus DNA polymerase.