Repurposing the human immunodeficiency virus (HIV) integrase inhibitor raltegravir for the treatment of felid alphaherpesvirus 1 (FHV-1) ocular infection

Pennington, Matthew Robert

Repurposing the human immunodeficiency virus (HIV) integrase inhibitor raltegravir for the treatment of felid alphaherpesvirus 1 (FHV-1) ocular infection

Abstract

Herpesviruses infect many species, inducing a wide range of diseases. Herpesvirus-induced ocular disease, which may lead to blindness, commonly occurs in humans, dogs, and cats, and is caused by human alphaherpesvirus 1 (HHV-1), canid alphaherpesvirus (CHV-1), and felid alphaherpesvirus 1 (FHV-1), respectively. Rapid and effective antiviral therapy is of the utmost importance to control infection in order to preserve the vision of infected people or animals. However, current treatment options are suboptimal, in large part due to the difficulty and cost of de novo drug development and the lack of effective models to bridge work in in vitro cell cultures and in vivo. Repurposing currently approved drugs for viral infections is one strategy to more rapidly identify new therapeutics. Furthermore, studying ocular herpesviruses in cats is of particular importance, as this condition is a frequent disease manifestation in these animals and FHV-1 infection of the cat is increasingly being recognized as a valuable natural-host model of herpesvirus-induced ocular infection First, the current models to study ocular herpesvirus infections were reviewed. Next, the efficacy of raltegravir was evaluated using a novel corneal explant model. Raltegravir is a human immunodeficiency virus (HIV) integrase inhibitor that was recently shown to poses antiviral activity against human herpesviruses. Then, electric cell-substrate impedance sensing (ECIS) was evaluated as a novel methodology to study the replication kinetics of herpesviruses. It was also used to characterize a fluorescently labeled FHV-1, created using CRISPR/Cas9 genome. Next, it was found that raltegravir inhibits both viral DNA synthesis initiation and late gene expression, a mechanism consistent with inhibition of viral ICP8. Finally, RNA sequencing was used to explore the indirect effects of raltegravir on the host. It was found that raltegravir treatment promoted the expression of anti-angiogenic factors and altered the metabolism of the host cells, both of which may be beneficial therapeutically. These results, combined with a recent in vivo study in experimentally infected cats, demonstrates that raltegravir is a viable treatment option for FHV-1 and warrants further investigations into its clinical potential against other herpesviruses.

Date Issued

2018-08-30

Keywords

Veterinary science; electric cell-substrate impedance sensing (ECIS); explant; Felid alphaherpesvirus (FHV-1); ICP8; ocular herpesvirus; raltegravir; Virology

Committee Chair

Van de Walle, Gerlinde

Committee Member

Parrish, Colin Ross
Wagner, Bettina
Ledbetter, Eric C.

Degree Discipline

Immunology and Infectious Disease

Degree Name

Ph. D., Immunology and Infectious Disease

Degree Level

Doctor of Philosophy

Types

dissertation or thesis