The immunobiology of corneal HSV-1 infection and herpetic stromal keratitis

Abstract

SUMMARYHuman alphaherpesvirus 1 (HSV-1) is a highly successful neurotropic pathogen that primarily infects the epithelial cells lining the orofacial mucosa. After primary lytic replication in the oral, ocular, and nasal mucosal epithelial cells, HSV-1 establishes life-long latency in neurons within the trigeminal ganglion. Patients with compromised immune systems experience frequent reactivation of HSV-1 from latency, leading to virus entry in the sensory neurons, followed by anterograde transport and lytic replication at the innervated mucosal epithelial surface. Although recurrent infection of the corneal mucosal surface is rare, it can result in a chronic immuno-inflammatory condition called herpetic stromal keratitis (HSK). HSK leads to gradual vision loss and can cause permanent blindness in severe untreated cases. Currently, there is no cure or successful vaccine to prevent latent or recurrent HSV-1 infections, posing a significant clinical challenge to managing HSK and preventing vision loss. The conventional clinical management of HSK primarily relies on anti-virals to suppress HSV-1 replication, anti-inflammatory drugs (such as corticosteroids) to provide symptomatic relief from pain and inflammation, and surgical interventions in more severe cases to replace damaged cornea. However, each clinical treatment strategy has limitations, such as local and systemic drug toxicities and the emergence of anti-viral-resistant HSV-1 strains. In this review, we summarize the factors and immune cells involved in HSK pathogenesis and highlight alternate therapeutic strategies for successful clinical management of HSK. We also discuss the therapeutic potential of immunoregulatory cytokines and immunometabolism modulators as promising HSK therapies against emerging anti-viral-resistant HSV-1 strains.

Keywords: HSK; HSV-1; IFN-λ; ISGs; acyclovir-resistant HSV-1; herpes keratitis; immunopathology; interferons; neutrophils.

Fig 1

Representative images showing herpetic keratitis in clinical patients. Eye images showing epithelial keratitis with (A) dendritic ulcer and (B) recurrent epithelial keratitis with stromal involvement. Eye images show stromal keratitis with (C) prominent stromal infiltration near the paracentral area accompanied by vigorous, active limbal vascularization and (D) with necrotizing stromal keratitis. (E) Eye image showing endothelial keratitis with recurring and severe inflammation of the endothelium, showing marked corneal edema and Descemet folds. (F) Eye image showing neurotrophic keratitis having ulceration with elevated borders and stromal haze. [Panels A, C, D, E, and F are adapted from reference (14), published under a Creative Commons license.]

Fig 2

Slit lamp images of a clinical patient with HSK ulcer. (A) Image at the time of diagnosis shows recurrent stromal keratitis with a significant ulcer, stromal infiltration, vascularization, and corneal thinning. (B) Slit lamp image at the time of diagnosis stained with fluorescein and visualized using the blue filter (450 nm). The patient was then treated with a combination of oral ACV (800 mg, five times daily), topical 3% ACV ointment (applied four times daily), and 0.1% dexamethasone (administered three times daily) for a month. After 1 month, the oral ACV dosage was tapered gradually to 400 mg, four times daily, and topical ACV was discontinued. (C) Slit lamp image after 3 months of treatment showed complete healing of the ulcer with reduced stromal infiltration but stromal haze, thinning, and vascularization are still visible. (D) Slit lamp image after 3 months of treatment stained with fluorescein and visualized using the blue filter showing punctate keratopathy. (All panels adapted from reference 14, published under a Creative Commons license.)

Fig 3

Current treatment strategies for corneal HSV-1 infection. The acute stage of HSV-1 infection begins with viral replication. This stage is treated with oral or topical antivirals. The viral replication promotes inflammation in the cornea, which is treated with topical corticosteroids. The final stage of corneal HSV-1 infection is corneal neovascularization, which can be treated with VEGF-A inhibitors.

Fig 4

Chemokines and cytokines play a critical role in HSK. (A) The HSV-1 replication initiates the secretion of sequelae of chemokines and inflammatory cytokines by the corneal epithelial cells. (B) The innate immune cells infiltrate the cornea, further promote the antiviral response, and activate the adaptive immune response. (C) The adaptive immune cells secrete inflammatory cytokines, promoting the infiltration of neutrophils and damaging the cornea.