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.
Highlights
Herpes simplex virus 1 (HSV-1) infections are ubiquitous in the population world-wide and in the United States, where seroprevalence is 65% by age 50 [1]
1 and B7-2 driven by the HCMV IEp were inserted into the HSV-1 thymidine kinase open reading frame (ORF) 751 bp from the 59 ATG in plasmid p101086.7BglII
The resulting plasmids were cotransfected into S2 cells with full-length DNA from the replication-defective HSV-1 strain D41D29 [22], which contains a lacZ insertion in the ICP8 ORF and a nonsense linker in the vhs ORF (Figure 1A)
Summary
Herpes simplex virus 1 (HSV-1) infections are ubiquitous in the population world-wide and in the United States, where seroprevalence is 65% by age 50 [1]. Effective control of HSV infection depends on the antiviral T cell response. Antiviral vaccines must elicit or provide these signals in order to induce strong cell-mediated immunity. Glycoprotein, peptide, or plasmidbased vaccines can decrease corneal shedding of HSV-1 and reduce the severity of HSK [4,5,6,7]. DNA vaccines provide antigen to T cells, and induce costimulation molecule expression due to inherent CpG motifs. Viral glycoproteins or peptide epitopes provide only antigen, so they require mixture with adjuvant to supply the ‘‘danger signals’’ necessary to elicit costimulation and cytokines. Attenuated, replication-competent viruses as vaccines naturally stimulate responses to multiple epitopes and supply the necessary danger signals by virtue of their similarity to wildtype virus infection. Attenuated HSV-1 can still be amplified 10,000-fold in tissue culture [9], and can develop adventitious mutations [12], raising safety concerns about replication-competent agents as vaccines
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