In vitro and in vivo antiviral effects of CLEVir-X against porcine reproductive and respiratory syndrome virus

TL;DR

CLEVir-X, a drug, shows antiviral effects against a virus in pigs by disrupting virus replication and causing harmful mutations.

Contribution

CLEVir-X demonstrates both mutagenic and nonmutagenic antiviral effects against PRRSV in vitro and in vivo.

Findings

CLEVir-X inhibits PRRSV replication by disrupting IMPDH and inducing mutagenesis.

Oral CLEVir-X reduced PRRSV load and lung lesions in infected pigs.

CLEVir-X treatment increased mutation frequency in PRRSV genomes, reducing infectivity.

Abstract

•CLEVir-X inhibits PRRSV via disruption of IMPDH in vitro.•CLEVir-X induced in vitro mutagenesis of PRRSV, reducing infectivity.•Oral administration of CLEVir-X alleviated clinical signs, lung lesions and PRRSV load in experimentally infected pigs.

CLEVir-X inhibits PRRSV via disruption of IMPDH in vitro.

CLEVir-X induced in vitro mutagenesis of PRRSV, reducing infectivity.

Oral administration of CLEVir-X alleviated clinical signs, lung lesions and PRRSV load in experimentally infected pigs.

The aim of this study was to investigate the in vitro and in vivo antiviral effects of CLEVir-X, against porcine reproductive and respiratory syndrome virus (PRRSV). CLEVir-X is a nucleoside analogue and a dialdehyde form of xanthosine. CLEVir-X demonstrated antiviral action during the in vitro portion of this experiment with its inosine monophosphate dehydrogenase (IMPDH) inhibition against PRRSV. The anti-PRRSV effect of CLEVir-X was recovered through supplementation with guanosine. This suggests that PRRSV replication may be regulated through IMPDH and its guanosine biosynthetic pathway. CLEVir-X treatment in cultures resulted in mutation frequency increase of up to 7.8-fold within the viral genomes (e.g. ORF6) compared to their parallel, untreated cultures. The incorporation of CLEVir-X into the viral genome causes lethal mutagenesis and subsequent decrease in specific infectivity. During the in vivo antiviral experiment, 21-day-old pigs began oral administration of 5 mL of phosphate buffered saline containing CLEVir-X (with purity of 68 % and dosage of 40 mg/kg body weight). This treatment was provided twice daily at 9:00AM and 5:00PM for 14 days. Pigs were simultaneously intranasally inoculated with PRRSV at the beginning of CLEVir-X treatment (21 days of age). Several beneficial effects from the oral administration of CLEVir-X were observed including reduction of body temperature, alleviation of respiratory clinical signs, decreased PRRSV load in both blood and lung tissues, and mitigation of lung interstitial pneumonia lesions. The results of the present study demonstrated that CLEVir-X has mutagenic and nonmutagenic modes of antiviral action against PRRSV based on both in vitro and in vivo antiviral experiments.

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