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

HSK Therapies: Current & Future

Antiviral nucleoside analogs, such as acyclovir, are the mainstay of treatment for HSV-1 ocular disease. In addition to antivirals, the Herpetic Eye Disease Study formally demonstrated an added benefit of topical corticosteroids in the treatment of HSK.[63] However, topical steroids have potentially serious ocular side effects, including development of cataracts and glaucoma. Therefore, alternative therapies for HSK are needed.

Given the CD4 T-cell-mediated pathogenesis of HSK, topical cyclosporin A, in addition to antivirals, may prove to be an effective alternative therapeutic option. Cyclosporin A has proven beneficial in cases of HSK resistant to corticosteroids in a small number of case reports, although randomized clinical trials are required to confirm these results.[64] Antiangiogenic agents, such as the anti-VEGF monoclonal antibody bevacizumab, have also been proposed as potential therapies, since corneal angiogenesis is an important factor in the development of HSK. Indeed, in a rabbit model of HSK,[8] and at least one human case report,[65] treatment with bevacizumab reduced corneal hemangiogenesis and inflammation following corneal HSV infection.

For patients in which all other treatment options have failed, full-thickness corneal transplantation, also know as penetrating keratoplasty, may be employed as a last resort to restore corneal clarity. However, corneal transplantation in patients with a history of HSK has a significantly higher graft failure rate compared with transplants for noninflammatory indications.[66] Further research investigating the immune mechanisms responsible for the more frequent and accelerated graft rejection in hosts previously infected with HSV is required.

Given the recurrent nature of HSK, an ideal therapy would prevent future attacks. The Herpetic Eye Disease Study demonstrated a significant reduction in HSK recurrences in patients prescribed prophylactic acyclovir for 1 year.[12] However, the prophylactic acyclovir regimen includes long-term twice-daily dosing, and compliance is often a problem, especially when medications are prescribed in the absence of symptoms. Perhaps the most exciting approach for a prophylactic HSK treatment lies in a therapeutic vaccination strategy, designed to boost the host immune response against HSV-1 to inhibit recurrent bouts of viral reactivation and corneal scarring. CD8 T cells surround HSV-1 latently infected neurons within murine[67] and human ganglia,[68] and are critically important for the noncytolytic inhibition of HSV-1 reactivation from neuronal latency.[69,70] Therefore, a vaccine designed to stimulate the HSV-specific CD8 T-cell population within latently infected ganglia may serve to inhibit reactivation events, as well as subsequent bouts of corneal inflammation and scarring, without damaging nonregenerating neurons. However, this option must be approached with caution, as inadvertent activation of CD4 T cells may exacerbate inflammation within the cornea. Thus, a more comprehensive understanding of the mechanisms of CD4 T-cell activation within the cornea during HSK is required to assure safe development of a therapeutic vaccine.


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