Current and Emerging Therapies for Ocular Herpes Simplex Virus Type-1 Infections

Abstract

Herpes simplex virus type-1 (HSV-1) is a neurotropic, double-stranded DNA virus that can cause a wide variety of diseases, including many ocular pathologies. It is one of the leading causes of infectious blindness in the United States. Because of its ubiquitous nature and its potential to cause serious ocular maladies, there is a significant need for more effective antiviral therapies against ocular HSV-1. In this review, we discuss the lifecycle of HSV-1 as it pertains to corneal infections and the clinically approved as well as emerging treatments to combat HSV-1 infections. We also highlight some newly identified host targets for the antiviral drug development.

Keywords: acyclovir; antiviral; herpes simplex virus; herpesvirus; keratitis; ocular therapy.

Figure 1

Schematics of herpes simplex virus type-1 (HSV-1) primary and recurrent infection. (1) The HSV-1 virions enter the cornea and initially replicate in the epithelium. (2) They then travel through the ciliary and ophthalmic nerves to the trigeminal ganglion in a retrograde fashion. (3) The virions establish a latent infection that can last for the lifetime of the host. (4) Stress-induced stimuli periodically reactivate the virus. (5) Reactivated virions travel through the ophthalmic and ciliary nerves in an anterograde fashion often to reach back to the site of initial infection. (6) HSV-1 re-infects the cornea, possibly leading to more pathologic symptoms, such as corneal scarring or neovascularization.

Figure 2

Schematics of the HSV-1 lifecycle and the steps targeted by antiviral agents. HSV-1 begins the entry process by attaching to heparan sulfate (HS) moieties located on proteoglycans on the cell surface. HSV-1 can also attach to HS chains on filopodia and engage in “viral surfing” along the filopodia to the cell surface. Once the HSV-1 glycoproteins have attached to their appropriate receptors, the viral envelope fuses with the host cell membrane, releasing the tegument and nucleocapsid into the cytoplasm. Viral entry can be inhibited (Box 1). Once in the cell, the capsid travels to the nucleus and injects the viral genome into it. HSV-1 then undergoes a process of circularizing, concatemerization, and packaging its genome into new capsids. During this period, the virus also transcribes mRNA and translates it, creating new proteins. Acyclovir and CRISPR/Cas9 inhibit vDNA replication, while BX795 impedes viral translation (Boxes 2 and 3, respectively). Once the new virions are produced, they travel from the nucleus through the ER and the Golgi apparatus, acquiring an envelope in the process. The enveloped virions then bud from the cell at specific locations. Presence of HS chains on the cell surface can trap virions, which is why HSV-1 upregulates heparanase (HPSE) during the later stages of infection to cleave the chains and promote egress. Viral egress is therefore inhibited by OGT 2115 (Box 4), a drug which inhibits the enzymatic activity of HPSE.