Psychological Stress and Other Potential Triggers for Recurrences of Herpes Simplex Virus Eye Infections

Objective To assess psychological stress and other factors as possible triggers of ocular herpes simplex virus (HSV) recurrences. Design A prospective cohort study nested in a randomized, placebo-controlled, clinical trial. Setting Fifty-eight community-based or university sites. Participants Immunocompetent adults (N = 308), aged 18 years or older, with a documented history of ocular HSV disease in the prior year and observed for up to 15 months. Exposure Variables Psychological stress, systemic infection, sunlight exposure, menstrual period, contact lens wear, and eye injury recorded on a weekly log. The exposure period was considered to be the week before symptomatic onset of a recurrence. Main Outcome Measure The first documented recurrence of ocular HSV disease, with exclusion of cases in which the exposure week log was completed late after the onset of symptoms. Results Thirty-three participants experienced a study outcome meeting these criteria. Higher levels of psychological stress were not associated with an increased risk of recurrence (rate ratio, 0.58; 95% confidence interval, 0.32-1.05; P = .07). No association was found between any of the other exposure variables and recurrence. When an analysis was performed including only the recurrences (n = 26) for which the exposure week log was completed late and after symptom onset, there was a clear indication of retrospective overreporting of high stress (P = .03) and systemic infection (P = .01). Not excluding these cases could have produced incorrect conclusions due to recall bias. Conclusions Psychological stress does not appear to be a trigger of recurrences of ocular HSV disease. If not accounted for, recall bias can substantially overestimate the importance of factors that do not have a causal association with HSV infection. HERPES SIMPLEX virus (HSV) is a leading cause of eye infections and visual loss. An important contributor to visual loss from HSV infection is its recurring nature. Several factors have been suggested as potential triggers of recurrent ocular, orofacial, or genital HSV disease, including upper respiratory tract infection, fever, sunlight, seasonal conditions, emotional factors, psychological stress, trauma, and menstruation. However, results from these studies have been inconsistent, and only a few studies have assessed ocular HSV recurrences. In a randomized, placebo-controlled, clinical trial, we found that 12 months of oral acyclovir therapy was beneficial in reducing the incidence of ocular HSV recurrences in participants with a recent history of active ocular HSV disease. In both treatment groups, the number of prior episodes of HSV eye disease was the only baseline or historical factor that was a strong predictor of a recurrence. Herein, we report the results of a prospective cohort study, nested within this clinical trial, that assessed psychological stress and other factors as possible triggers of recurrent HSV eye disease

Herpetic Corneal Opacities

Herpes Simplex viral keratitis is one of the most common infectious causes of corneal blindness [1, 2] involving 0.1% of the general population and inducing significant reduction in vision in 1 out 6 of the affected patient

Therapeutic Immunization with a Mixture of Herpes Simplex Virus 1 Glycoprotein D-Derived “Asymptomatic” Human CD8 +

Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the efficacy of a therapeutic vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8(+) T cells from “naturally” protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8(+) T-cell epitopes (gD(53–61), gD(70–78), and gD(278–286)) were linked with a promiscuous CD4(+) T-cell epitope (gD(287–317)) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N(ε)-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8(+) T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8(+) T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1(+) TIM-3(+) CD8(+) T cells. The results underscore the potential of an ASYMP CD8(+) T-cell epitope-based therapeutic vaccine strategy against recurrent ocular herpes. IMPORTANCE Seventy percent to 90% of adults harbor herpes simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide vaccine that contains exclusively human “asymptomatic” CD8(+) T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic herpes vaccine

Effect of Famciclovir on Herpes Simplex Virus Type 1 Corneal Disease and Establishment of Latency in Rabbits

Famciclovir (FCV) is efficacious in the treatment of acute herpes zoster and recurrent genital infections but has not been used to treat ocular herpes simplex virus (HSV) infections. We evaluated the efficacy of orally administered FCV in treating HSV-1 epithelial keratitis and determined its effects on the establishment of latency and subsequent reactivation. Rabbits were inoculated with HSV-1 strain 17 syn+ and treated twice daily with increasing concentrations of FCV (60 to 500 mg/kg of body weight). This resulted in a significant, dose-dependent improvement in keratitis scores, as well as prolonged survival. Regardless of the dose of drug used, all groups exhibited the high rates of spontaneous and induced reactivation characteristic of 17syn+. The efficacy of 250 mg of FCV per kg was also compared to topical treatment with 1% trifluorothymidine (TFT). Although TFT treatment was more effective at reducing eye disease, FCV-treated rabbits had a better survival rate. Real-time quantitative PCR analysis of rabbit trigeminal ganglia (TG) demonstrated that FCV significantly reduced the HSV-1 copy number compared to that after treatment with TFT or the placebo but not in a dose-dependent manner. In summary, oral FCV treatment significantly reduces the severity of corneal lesions, reduces the number of HSV-1 genomes in the TG, improves survival, and therefore may be beneficial in reducing the morbidity of HSV keratitis in the clinic