The role of interferon in the protective effect of a synthetic double-stranded polyribonucleotide against intranasal vesicular stomatitis virus challenge in mice

Abstract

A B S T R A C T Intravenous injection of polyinosinic acid/polycytidylic acid [(poly rI) * (poly rC)] offered significant protection against intranasal challenge of young mice with vesicular stomatitis virus (VSV). Optimal protection was obtained when a single dose was administered 2 hr before virus challenge, but repeated doses were effective when started as late as 3 days after virus challenge. The therapeutic ratio or ratio of maximum tolerated dose to minimum effective dose for a single intravenous injection of (poly rI) *(poly rC) 2 hr before virus inoculation was > 8 mg/kg: 0.004 mg/ kg or > 200. Dose-response curves for interferon production and antiviral protection by (poly rI) -(poly rC) were closely parallel. Equivalent doses of poly rI or poly rC alone did not exert any interferon-inducing capacity or protective effect on intranasal VSV challenge. Several factors, which are known to potentiate or antagonize interferon production, increased or decreased the interferon-inducing capacity and antiviral protection of either (poly rI) * (poly rC) or maleic acid/divinyl ether copolymer (MA/DVE) in parallel. Interferon production and antiviral protection by MA/DVE were enhanced by arginine but abolished by prior treatment with MA/DVE; DEAE-dextran (intraperitoneally), kinetin riboside and isopentenyladenosine, and prior injection of endotoxin reduced both interferon production and antiviral protection by (poly rI) -(poly rC).Treatment with exogenous interferon in amounts which closely mimicked the levels of circulating interferon produced endogenously by an effective dose of (poly rI) * (poly rC) gave protection against intranasal

Studies on the Toxicity and Antiviral Activity of Various Polynucleotides

“…To evaluate the therapeutic significance of the polynucleotides described in Table 2, we measured their relative antiviral activities and toxicities in mice. As was stated previously, mice receiving a tail vein injection of (poly rI) * (poly rC) are protected by the production of interferon against a subsequent intranasal VSV challenge (7). With this model, it is likely that the antiviral activity of the other polynucleotides should also be due to their ability to produce interferon.…”

“…How justified is this assumption? Previously it was shown in 10-g mice that production of interferon by 0.5 jsg of (poly ri) * (poly rO) was approximately equivalent to the injection of 1,400 units of exogenous mouse interferon (7). The LD5o for (poly rI) * (poly rC) in 10-g mice (200 Mg) would be equivalent to the administration of much greater quantities of exogenous interferon.…”

“…Swiss-Webster mice weighing 10 g (five per group) were injected with 4 pg of designated polynucleotide; 2 hr later, mice were bled, and combined sera in each group were assayed for interferon on L cells with a plaque reduction assay (7). Interferon titers were expressed as in the in vitro assay.…”

An Odyssey in antiviral drug development—50 years at the Rega Institute: 1964–2014

“…He showed an unbridable enthusiasm for whatever result or finding I came up with, so that after 2 years at Stanford I had managed to publish about 25 papers, all with T.C. Merigan as co-author, two papers in Nature 8 , 9 , one in Science 10 , and a couple others in such distinguished journals as JCI ( Journal of Clinical Investigation ) 11 and JMB ( Journal of Molecular Biology ) 12 . I did not have other obligations except for working hard (enjoying myself) in the laboratory and producing manuscripts, which at one occasion, after I had finished writing it, my wife typed during the night, so that when T.C.…”