New Paradigms for the Study of Ocular Alphaherpesvirus Infections: Insights into the Use of Non-Traditional Host Model Systems

Abstract

Ocular herpesviruses, most notably human alphaherpesvirus 1 (HSV-1), canid alphaherpesvirus 1 (CHV-1) and felid alphaherpesvirus 1 (FHV-1), infect and cause severe disease that may lead to blindness. CHV-1 and FHV-1 have a pathogenesis and induce clinical disease in their hosts that is similar to HSV-1 ocular infections in humans, suggesting that infection of dogs and cats with CHV-1 and FHV-1, respectively, can be used as a comparative natural host model of herpesvirus-induced ocular disease. In this review, we discuss both strengths and limitations of the various available model systems to study ocular herpesvirus infection, with a focus on the use of these non-traditional virus-natural host models. Recent work has demonstrated the robustness and reproducibility of experimental ocular herpesvirus infections in dogs and cats, and, therefore, these non-traditional models can provide additional insights into the pathogenesis of ocular herpesvirus infections.

Pilot Study of the Safety and Tolerability of a Subconjunctival Penciclovir Implant in Cats Experimentally Infected with Herpesvirus

“…FHV-1 model is reliable. 46 Data from cats in this study with blank implants were not obviously different from data from untreated cats in previous studies. This permitted us to hypothesize that differences seen in this pilot study between blank-and penciclovir-implanted cats were likely associated directly with the implant or penciclovir; however, other explanations are possible and should be tested in future studies in which uninfected implanted cats are assessed.…”

An eye on the dog as the scientist's best friend for translational research in ophthalmology: Focus on the ocular surface

“…297 These factors likely explain why rabbits and rodents-traditionally used to model ocular surface infections in humans-cannot fully recapitulate the disease presentation and progression that occur in human patients. 81,298 As such, there is an emerging appreciation for the translational advantage of studying spontaneous (and not experimental) ocular infections in dogs:…”

“…• Herpetic keratitis: Recent work has highlighted the robustness and reproducibility of the canine model to study ocular herpesvirus infections and disease, 81,82 showing striking similarities in the pathogenesis of canine herpesvirus-1 and herpes simplex virus-1, both members of the alphaherpesvirinae subfamily with a seroprevalence of 21-98% in dogs (CHV-1) and 67-90% in humans (HSV-1). 81 • Bacterial keratitis: The most common bacterial genera isolated from canine patients overlap with the ones recognized in human patients (Staphylococcus, Streptococcus, and Pseudomonoas). 83,153 In fact, the major culprit in canine bacterial keratitis (Staphylococcus pseudintermedius) is now considered an emerging zoonosis in humans.…”

“…Dogs are expensive to purchase and maintain in specific housing, the molecular tool kit specific to dogs is more limited compared to traditional laboratory animals (mice, rats, and rabbits), and there are important ethical and public-perception considerations associated with the use of dogs as experimental animal models. 6,81,287,288,320 Further, most canine subjects have a mixed genetic background (outbred) that can affect the variability in disease characteristics (e.g., severity, response to therapy); in contrast, rodents and rabbits have readily available inbred strains with the same genetic makeup, as well as knockout and transgenic strains that allow investigators to explore details of pathways and factors involved in disease pathogenesis. 81,201 Last, clinical trials involving dogs can be limited by rigorous scientific and ethical review, unpredictable case enrollment, variability in disease phenotype among patients, economic challenges (e.g., owner ability to provide care), and owner compliance, to name a few.…”

The HIV Integrase Inhibitor Raltegravir Inhibits Felid Alphaherpesvirus 1 Replication by Targeting both DNA Replication and Late Gene Expression

“…Felid alphaherpesvirus 1 (FeHV-1) causes ocular infections in cats, and due to the analogous presentations of the diseases in humans and cats, FeHV-1 is increasingly considered to be a useful natural-host model of ocular alphaherpesvirus infection (22,23). Like HHV-1, FeHV-1 has similar challenges for successful treatment (24,25).…”