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

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

Disclosures

Future Virology. 2010;5(6):699-708. 

In This Article

Future Perspective

Our understanding of the molecular mechanisms involved in corneal HSV infection, and the subsequent pathologic immune response, has grown significantly in recent years, and this information has yielded several novel therapeutic targets. However, several very important aspects of HSK pathogenesis remain obscure. For instance, the specificity of the CD4 T-cell response within the cornea remains controversial, with some investigators postulating that bystander activation of any CD4 T cells can cause HSK, while others maintain that pathologic CD4 T cells are specific for HSV antigens. Several laboratories are currently in the process of generating transgenic mice with T-cell receptors specific for viral antigens, recognized by HSV-specific CD4 T cells. These mice should provide a wealth of knowledge regarding the specificity of the pathologic CD4 T-cell response, which may then be targeted therapeutically.

Despite the multitude of research investigating HSK pathogenesis, the standard of care for acute bouts of HSK has not changed in decades. This regimen consists of antivirals to combat the virus and steroids to inhibit the pathologic immune response. Several alternative therapies have been tested in animal models or small case series in humans, but, to our knowledge, no randomized trials have been completed. These alternative treatments include cyclosporin A, which inhibits CD4 T-cell activation, and bevacizumab, an anti-VEGF monoclonal antibody that inhibits angiogenesis. Given the diverse mechanisms of action of these agents, it is likely that combination therapy would provide the most efficacious results. For instance, a triple-drug therapy targeting viral replication with acyclovir, the pathologic CD4 T-cell response with cyclosporin A, and angiogenesis with bevacizumab, could potentially block three major processes in HSK pathogenesis. Obviously, further validation of these agents requires randomized clinical trials.

Recurrent bouts of HSV reactivation with subsequent corneal scarring is thought to mediate blinding HSK. Furthermore, prophylactic treatment with acyclovir reduces the incidence of HSK events, suggesting that viral replication is required for disease, and that blockade of viral reactivation from latency would decrease disease burden. We, and others, have defined a critical role for the immune system, and CD8 T cells in particular, in preventing HSV reactivation from neuronal latency. Thus, a therapeutic vaccine designed to boost the host CD8 T-cell response against latent HSV could potentially block viral reactivation and subsequent corneal disease. This is an especially enticing option, since this type of vaccine would likely require only a single dose for long-term protection compared with the twice-daily dosing of acyclovir required to prevent HSK events. However, a more detailed understanding of the pathologic immune response within the cornea is required to ensure that such a vaccine does not inadvertently activate immunopathologic CD4 T cells, thereby exacerbating HSK. Despite our current detailed understanding of HSK pathogenesis, further research is required to fully understand the mechanism of this blinding disease, which will hopefully allow for development of a cure.

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