B7 Costimulation Molecules Encoded by Replication-Defective, vhs-Deficient HSV-1 Improve Vaccine-Induced Protection against Corneal Disease

Abstract

Herpes simplex virus 1 (HSV-1) causes herpes stromal keratitis (HSK), a sight-threatening disease of the cornea for which no vaccine exists. A replication-defective, HSV-1 prototype vaccine bearing deletions in the genes encoding ICP8 and the virion host shutoff (vhs) protein reduces HSV-1 replication and disease in a mouse model of HSK. Here we demonstrate that combining deletion of ICP8 and vhs with virus-based expression of B7 costimulation molecules created a vaccine strain that enhanced T cell responses to HSV-1 compared with the ICP8−vhs− parental strain, and reduced the incidence of keratitis and acute infection of the nervous system after corneal challenge. Post-challenge T cell infiltration of the trigeminal ganglia and antigen-specific recall responses in local lymph nodes correlated with protection. Thus, B7 costimulation molecules expressed from the genome of a replication-defective, ICP8−vhs− virus enhance vaccine efficacy by further reducing HSK.

Herpes Simplex Virus 1 ICP22 but Not US1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

“…At day 28 postinfection, TG were collected, and DNA was isolated from each TG as previously described (25). PCR primers specific for the HSV-1 UL50 gene were used to measure viral DNA loads (26), and primers for the mouse adipsin gene were used as a loading control (27). Real-time PCR was performed in a total volume of 25 l per sample of FastStart SYBR green Master (Roche, Indianapolis, IN) and primers in a StepOnePlus Real-Time PCR System (Applied Biosystems).…”

The current state of vaccine development for ocular HSV-1 infection

“…However, evidence from a prophylactic replication disabled whole virus vaccine in mice suggests that enhanced cell mediated immune responses not only resolve acute infection in the TG but also reduce the severity of HSK following challenge [90]. On the other hand, much literature has implicated CD4 + T cells in the pathogenesis of HSK in the mouse model of ocular HSV-1 infection [82].…”

The Immunologic Basis for Severe Neonatal Herpes Disease and Potential Strategies for Therapeutic Intervention

“…However, it is not clear whether some of these alterations of the virus may remove important targets of human immunity. Other modifications to the viral genome, such as inserting a dominant-negative mutant gene [229] or inserting costimulatory genes [230, 231], may carry the risk of gene transfer to a wild-type virus through heterologous recombination [232]. Novel delivery systems or adjuvants need to be produced in a cost-effective manner, require careful evaluation for safety in humans, and may promote unacceptable inflammatory responses [233].…”