Protection against Recurrent Ocular Herpes Simplex Virus Type 1 Disease after Therapeutic Vaccination of Latently Infected Mice

Abstract

The potential of therapeutic vaccination of animals latently infected with herpes simplex virus type 1 (HSV-1) to enhance protective immunity to the virus and thereby reduce the incidence and severity of recurrent ocular disease was assessed in a mouse model. Mice latently infected with HSV-1 were vaccinated intranasally with a mixture of HSV-1 glycoproteins and recombinant Escherichia coli heat-labile enterotoxin B subunit (rEtxB) as an adjuvant. The systemic immune response induced was characterized by high levels of virusspecific immunoglobulin G1 (IgG1) in serum and very low levels of IgG2a. Mucosal immunity was demonstrated by high levels of IgA in eye and vaginal secretions. Proliferating T cells from lymph nodes of vaccinated animals produced higher levels of interleukin-10 (IL-10) than were produced by such cells from mockvaccinated animals. This profile suggests that vaccination of latently infected mice modulates the Th1-dominated proinflammatory response usually induced upon infection. After reactivation of latent virus by UV irradiation, vaccinated mice showed reduced viral shedding in tears as well as a reduction in the incidence of recurrent herpetic corneal epithelial disease and stromal disease compared with mock-vaccinated mice. Moreover, vaccinated mice developing recurrent ocular disease showed less severe signs and a quicker recovery rate. Spread of virus to other areas close to the eye, such as the eyelid, was also significantly reduced. Encephalitis occurred in a small percentage (11%) of mock-vaccinated mice, but vaccinated animals were completely protected from such disease. The possible immune mechanisms involved in protection against recurrent ocular herpetic disease in therapeutically vaccinated animals are discussed.

Memory CD8 T-Cell Differentiation during Viral Infection

“…Similarly, providing more antigen to CD8 T cells that are continuously stimulated in vivo and functionally impaired may, in fact, worsen the exhaustion. Indeed, with a recent notable exception (75), therapeutic vaccination has rarely provided benefit when the antigen load is high (32,56,61,126), and most positive results have been achieved when viral replication is suppressed either by drug treatment or latency (52,63,93,114). As with preventive vaccination, the proliferative potential of responding T cells will be an important factor determining the outcome of therapeutic vaccinations (116).…”

Low CD8 T-Cell Proliferative Potential and High Viral Load Limit the Effectiveness of Therapeutic Vaccination

“…Several studies have examined the potential benefits of therapeutic vaccination during a variety of persistent infections (6,9,15,18,20,22,24,28,30,31,38,40). On one hand, some reports have demonstrated enhanced immune responses following therapeutic vaccination.…”

Acute Morphine Administration Reduces Cell-Mediated Immunity and Induces Reactivation of Latent Herpes Simplex Virus Type 1 in BALB/c Mice

“…So, this time and dose were selected to evaluate the effects of acute morphine administration on immune responses to HSV-1 reactivation in the nearest time after acute morphine administration with maximum of immunosuppression. Reactivation of HSV-1 from latency may be closely tied to the effect of glucocorticoids on the immune response (26). It is now clear that opioids have a wide array of immunomodulatory effects on the innate and acquired immune systems through the hypothalamic-pituitary-adrenal axis by increasing glucocorticoid levels (13,14).…”

“…In this study, we use one single dose of 75 mg/kg morphine, based on previous studies that have shown this dose induces maximum immunosuppression in mice (7). Richards et al have shown that HSV reactivation induces cellular immunity 4 to 7 days after reactivation (26). Therefore, in order to prevent interference between the primary immune response and secondary immunity induced during HSV reactivation, the effects of morphine administration on immune responses to HSV-1 reactivation were evaluated quickly (12 h) after the injection of morphine.…”