Large Amounts of Reactivated Virus in Tears Precedes Recurrent Herpes Stromal Keratitis in Stressed Rabbits Latently Infected with Herpes Simplex Virus

Abstract

Aim Recurrent herpetic stromal keratitis (rHSK), due to an immune response to reactivation of herpes simplex virus (HSV-1), can cause corneal blindness. The development of therapeutic interventions such as drugs and vaccines to decrease rHSK have been hampered by the lack of a small and reliable animal model in which rHSK occurs at a high frequency during HSV-1 latency. The aim of this study is to develop a rabbit model of rHSK in which stress from elevated temperatures increases the frequency of HSV-1 reactivations and rHSK. Materials and methods Rabbits latently infected with HSV-1 were subjected to elevated temperatures and the frequency of viral reactivations and rHSK were determined. Results In an experiment in which rabbits latently infected with HSV-1 were subjected to ill-defined stress as a result of failure of the vivarium air conditioning system, reactivation of HSV-1 occurred at over twice the normal frequency. In addition, 60% of eyes developed severe rHSK compared to <1% of eyes normally. All episodes of rHSK were preceded four to five days prior by an unusually large amount of reactivated virus in the tears of that eye and whenever this unusually large amount of reactivated virus was detected in tears, rHSK always appeared 4–5 days later. In subsequent experiments using well defined heat stress the reactivation frequency was similarly increased, but no eyes developed rHSK. Conclusions The results reported here support the hypothesis that rHSK is associated not simply with elevated reactivation frequency, but rather with rare episodes of very high levels of reactivated virus in tears 4–5 days earlier.

Bilateral tear film alterations in patients with unilateral quiescent herpes simplex keratitis

“…; Perng et al. ). It is unlikely that non‐reactivated virus can cause sufficient ocular inflammation and induce tear modifications observed in the unaffected eyes.…”

“…Thus, there is hypothesis that the contralateral unaffected eyes may have an asymptomatic herpetic involvement which may cause ocular inflammation and eventually lead to dry eye. However, the virus in tears is transient and not reactivated (Kumar et al 2010;Kaufman et al 2005;Perng et al 2015). It is unlikely that non-reactivated virus can cause sufficient ocular inflammation and induce tear modifications observed in the unaffected eyes.…”

A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a “Humanized” HLA Transgenic Rabbit Model

“…4 From a practical standpoint, the size of rabbit cornea is significantly larger than those of mice and offer plentiful amount of tissues for phenotypic and functional characterization of HSV-specific T cells using individual tissues. 17,[45][46][47][48] In addition, compared to mice, the surfaces of the rabbit and human eye are relatively immunologically isolated from systemic immune responses. 47 To overcome the hurdle that rabbits do not mount T-cell responses specific to human HLA-restricted human epitopes, we recently introduced a novel ''humanized'' HLA-Tg rabbit model of ocular herpes in which the rabbits express HLA (HLA class I molecules).…”

Prior Corneal Scarification and Injection of Immune Serum are Not Required Before Ocular HSV-1 Infection for UV-B-Induced Virus Reactivation and Recurrent Herpetic Corneal Disease in Latently Infected Mice

“…1–4 Following a primary ocular infection, HSV-1 travels up axons to the trigeminal ganglia (TG) where it establishes lifelong latency. 1,5 Sporadic HSV-1 reactivations result in virus returning to and replicating in the cornea. 1 At this time, infectious virus can be detected in tear films by swabbing and plating the tears on monolayers of tissue culture indicator cells.…”

“…1 At this time, infectious virus can be detected in tear films by swabbing and plating the tears on monolayers of tissue culture indicator cells. 5 Individuals harboring these latent HSV-1 infections have frequent episodes of spontaneous reactivation and virus shedding in tears – as often as 3 out of every 10 days (30%). 3 Fortunately, most HSV-1 reactivations and shedding do not lead to clinical symptoms (i.e.…”