Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Recurrent viral diseases often occur after the viruses evade the hosts' immune system, by inducing exhaustion of antiviral T cells. In the present study, we found that functionally exhausted herpes simplex virus type 1 (HSV-1) -specific CD8+ T cells, with elevated expression of lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, following UV-B induced virus reactivation from latency the symptomatic wild-type (WT) B6 mice that developed increase virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific LAG-3+CD8+ T cells in both trigeminal ganglia (TG) and cornea. Moreover, a therapeutic blockade of LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB498-505 peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional HSV-1 gB498-505 specific CD8+ T cells in both TG and cornea and protected against UV-B induced recurrent corneal herpes infection and disease. In contrast to dysfunctional HSV-specific CD8+ T cells from WT B6 mice, more functional HSV-specific CD8+ T cells were detected in LAG-3-/- deficient mice and were associated with less UV-B induced recurrent corneal herpetic disease. Thus, the LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergizes with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.

Effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with canine herpesvirus-1.

Latent canine herpesvirus-1 (CHV-1) infections are common in domestic dogs, but stimuli causing viral reactivation and recrudescent disease are poorly understood. Immunosuppressive pharmaceuticals are currently the only experimentally established triggers for recurrent ocular CHV-1 infection in dogs; however, ocular CHV-1 shedding has been reported clinically following strontium-90 beta radiotherapy of the ocular surface and it has been speculated that radiotherapy can directly induce viral reactivation. Strontium-90 is used as a beta radiation source for the treatment of a variety of neoplastic and immune-mediated canine ocular surface diseases. In the present study, the effects of ocular surface strontium-90 beta radiotherapy in dogs latently infected with CHV-1 were evaluated. Ten mature dogs with experimentally induced latent CHV-1 infections were randomly divided into two groups: one group received a single fraction 50 Gy radiation dose in one application from a strontium-90 ophthalmic applicator and the second group received sham radiotherapy. Dogs were then monitored for 45 days for recurrent ocular CHV-1 infection using clinical and virological outcome measures. Clinical ophthalmic examinations, ocular sample CHV-1 PCR assays, and serum CHV-1 virus neutralizing antibody assays were performed at specified intervals. No abnormalities suggestive of recurrent CHV-1 ocular disease were observed on clinical examination in any dog during the study. Ocular viral shedding was not detected and CHV-1 virus neutralizing titers remained stable in all dogs. A single fraction 50 Gy radiation dose administered to the ocular surface by strontium-90 beta radiotherapy did not result in detectable recurrent ocular CHV-1 infection in mature dogs with experimentally induced latent infection.

The prevalence of herpes simplex virus shedding and infection in the oral cavity of seropositive patients undergoing head and neck radiation therapy.

OBJECTIVE: Herpes viruses are characterized by their ability to establish and maintain a latent infection that can reactivate. Only 2 preliminary studies have examined herpes simplex virus (HSV) reactivation in patients receiving head and neck radiotherapy. The role of radiation therapy in the reactivation of a latent virus has not been established. The purpose of the present study was to evaluate the incidence of HSV reactivation in patients receiving radiation treatment for head and neck malignancies. METHODS: Twenty patients, 19 of whom were HSV seropositive, undergoing head and neck radiation therapy were assessed weekly before and during radiation therapy, and HSV cultures were completed during cancer treatment. RESULTS: Only 3.6% of the cultures were positive for HSV during radiation therapy. HSV was cultured in 4 men receiving a mean of 6,000 cGy to the head and neck area. Recovery from HSV was seen in patients nearing completion of radiation therapy. CONCLUSIONS: The results of this study suggest that HSV reactivation is not common during radiation therapy. Therefore, this study does not support prophylaxis of HSV in patients undergoing head and neck irradiation.