Evaluation of feline-herpesvirus-1 for genomic mutations and antiviral resistance in cats treated with antiviral medications

Abstract

Purpose : Feline herpesvirus-1 (FHV-1) is a common cause of ocular surface disease (OSD) in domestic cats, similar to Herpes Simplex Virus (HSV -1/2) in humans. While HSV-1/2 can readily develop resistance to antiviral medications, this has not previously been documented for FHV-1.The purpose of this study was to detect mutations and development of resistance in FHV-1 obtained from naturally infected cats with OSD. Virus was isolated from cats enrolled in a prospective clinical trial of antiviral medications.

Methods : A cohort of 14 shelter cats with a median age of 3 months (6 females, 8 males) positive for FHV-1 with OSD were treated with one of three antiviral medications or placebo twice daily for one week. Treatment groups included cidofovir 0.5% ophthalmic solution (3), ganciclovir 0.15% ophthalmic solution (3), famciclovir oral suspension (5), or placebo (3). FHV-1 was isolated from each cat on day 1 prior to the start of treatment and after seven days of twice daily treatment (day 8) via conjunctival swabs. Viral DNA was extracted for sequencing via Illumina MiSeq with genomic variant detection between paired day 1 and day 8 isolates. Isolates with non-synonymous variants were tested in-vitro to determine half-maximal inhibitory concentrations (IC50).

Results : 171 synonymous mutations and 3 nonsynonymous mutations were identified between paired samples. Viral mutations developed at similar frequencies in cats receiving antiviral medications or placebo (p=0.49). No variants were detected in viral genes associated with viral replication. All 3 non-synonymous variants were located in the FHV-1 ICP4 gene (transcriptional regulator). Overall, the majority of isolate pairs (10/14) were near-identical. There was no evidence of antiviral drug resistance based on IC50 values in the 3 non-synonymous day 8 isolates.

Conclusions : Our results are consistent with previous data that the FHV-1 genome is extremely homogenous. Short-term use of twice daily topical or systemic antiviral medications in immunocompetent feline hosts appear unlikely to lead to significant viral mutation or development of antiviral drug resistance in FHV-1. In contrast to HSV-1/2, FHV-1 is highly stable. Further research into the underlying mechanisms of this finding have translational potential.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.