Herpes Stromal Keratitis: Erosion of Ocular Immune Privilege by Herpes Simplex Virus

Jared E Knickelbein; Kristine-Ann Buela; Robert L Hendricks


Future Virology. 2010;5(6):699-708. 

In This Article

Abstract and Introduction


Herpes stromal keratitis (HSK) is a potentially blinding disease caused by herpes simplex virus corneal infection. Most cases of HSK are due to reactivation of the virus from latency leading to recurrent bouts of corneal inflammation and scarring with progressive loss of vision. Replicating virus is required to initiate HSK, and CD4 T cells of the adaptive immune system appear requisite for stromal inflammation. Corneal neovascularization also contributes significantly to HSK pathogenesis. Combination therapy with topical antivirals and corticosteroids is the current standard of care for human HSK. Future therapies will probably target angiogenesis with anti-VEGF agents to inhibit blood vessel growth into the normally avascular cornea, and target viral reactivation with therapeutic vaccination strategies to inhibit subsequent attacks.


Herpes simplex virus type 1 (HSV-1) is an extraordinarily common human pathogen. Following infection of the orofacial region, such as the ocular surface or oral mucosa, the virus infects innervating sensory neurons and establishes a latent infection within the connecting trigeminal ganglion. Demonstrating the widespread prevalence of HSV-1 infection, analyses of postmortem human trigeminal ganglia revealed more than 70% positivity for HSV-1 DNA by PCR.[1,2] Periodic reactivation of latent virus within infected ganglia can lead to anterograde transport of the virus back to the periphery causing recrudescent disease, such as the common cold sore or herpetic keratitis. Rarely, HSV-1 may reactivate and travel to the CNS, causing potentially fatal encephalitis.

This article will focus on HSV-1 infection of the cornea and the resulting immunopathological disease, herpes stromal keratitis (HSK). The cornea serves several functions, including refraction of light to the retina to produce visual images, and as a barrier, preventing pathogens and foreign objects from entering the eye. To properly serve its visual function, the cornea must maintain clarity as well as proper shape and structure. The normal cornea consists of three layers: the outermost stratified epithelium; the middle stroma, mostly made up of precisely layered collagen fibrils; and the innermost endothelium, a single-cell-thick layer that pumps fluid from the collagenous stroma to maintain proper corneal thickness and clarity. The normal cornea contains a relatively small population of immune cells, which are mainly antigen-presenting cells, and lacks blood and lymph vessels. These qualities are partially responsible for the cornea's status as immunoprivileged. Any disruption of this normal architecture could lead to neovascularization and opacification of the cornea, resulting in diminished visual acuity. As discussed in detail later, HSV possesses the ability to disrupt corneal immunoprivilege by inducing a potent inflammatory response, in-growth of both blood and lymph vessels, and destruction of the normal stromal architecture (Figure 1).

Figure 1.

Progression of herpes stromal keratitis immunopathology following corneal herpes simplex virus-1 infection. (A) Transition 1: following HSV-1 corneal infection, innate immune cells are recruited and secrete cytokines and chemokines; infected epithelial cells secrete VEGF; and antigen-presenting cells capture viral antigens before trafficking to draining lymph nodes. (B) Transition 2: in response to chemokines, CD4 T cells infiltrate the cornea and orchestrate a more chronic inflammation dominated by neutrophils and facilitated by in-growth of blood and lymphatic vessels. (C) Transition 3: recurrent bouts of corneal inflammation result in stromal scarring and subsequent visual loss. (D) Transition 4: corneal transplantation may be attempted once scarring occurs, but immunomediated graft rejection is common in hosts with previous HSK. Ideally, future treatments will block HSK pathogenesis before scarring occurs.
APC: Antigen-presenting cell; HSK: Herpes stromal keratitis; HSV: Herpes simplex virus.


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