Evaluation of Antiviral Activity of Ivermectin against Infectious Bovine Rhinotracheitis Virus in Rabbit Model

SIMPLE SUMMARY: Infectious bovine rhinotracheitis is responsible for significant economic losses in the cattle industry worldwide, and several countries are working toward controlling or eradicating the infection. This study aimed to investigate whether ivermectin had a therapeutic effect on herpesvirus infections. Firstly, this study showed that low concentrations (6–25 nM) of IVM (ivermectin) can inhibit viral replication in infected cell culture in a dose-dependent way. Importantly, Japanese large-eared white rabbits were infected with 10(7.0)TCID(50)/mL of IBRV viral solution via nasal drops and then treated with different doses of ivermectin at different time points after the attack. Ivermectin treatment could have a therapeutic effect by decreasing clinical signs and viral shedding. IVM could be a candidate drug for early antiviral therapy against IBRV infection. ABSTRACT: Infectious bovine rhinotracheitis (IBR) caused by bovine herpes virus 1 (BoHV-1) can lead to enormous economic losses in the cattle industry. Vaccine immunization is preferentially used to decrease its transmission speed and resultant clinical signs, rather than to completely stop viral infection. Therefore, a drug effective in treating IBR is urgently needed. Our previous work demonstrated that ivermectin significantly inhibited viral replication in a cell infection model. This study aimed to investigate its antiviral effects in vivo by using a rabbit infection model. The viral inhibition assay was first used to confirm that ivermectin at low concentrations (6–25 nM) could reduce viral titers (TCID(50)) significantly (p < 0.001) at 24 h post-infection. In rabbits, ivermectin was administrated with one to three doses, based on the recommended anti-parasite treatment dosage (0.2 mg/kg bodyweight) through subcutaneous injection at different days post-infection in the treated IBRV infection groups, while non-treated infection group was used as the control. The infected rabbits showed hyperthermia and other clinical signs, but the number of high-fever rabbits in the ivermectin treatment groups was significantly lower than that in the non-treated infection group. Furthermore, in ivermectin treatment groups, the cumulative clinical scores correlated negatively with drug doses and positively with delay of administration time post-infection. The overall nasal shedding time in ivermectin-treated groups was two days shorter than the non-treated challenge group. At the same time point, the titer of neutralizing antibodies in the treatment group with triple doses was higher than the other two-dose groups, but the difference between the treatment groups decreased with the delay of drug administration. Correspondingly, the serious extent of lung lesions was negatively related to the dosage, but positively related to the delay of drug administration. The qPCR with tissue homogenates showed that the virus was present in both the lung tissues and trigeminals of the infected rabbits. In conclusion, ivermectin treatment had therapeutic effect by decreasing clinical signs and viral shedding, but could not stop virus proliferation in lung tissues and trigeminals.