Noncognate Signals Drive Enhanced Effector CD8(+) T Cell Responses through an IFNAR1-Dependent Pathway after Infection with the Prototypic Vaccine, 0 Delta NLS, against Herpes Simplex Virus 1

Previous studies by our group identified a highly efficacious vaccine 0 Delta NLS (deficient in the nuclear localization signal of infected cell protein 0) against herpes simplex virus 1 (HSV-1) in an experimental ocular mouse model. However, details regarding fundamental differences in the initial innate and adaptive host immune response were not explored. Here, we present a side-by-side analysis of the primary infection characterizing differences of the host immune response in mice infected with 0 Delta NLS versus the parental, GFP105. The results show that local viral infection and replication are controlled more efficiently in mice exposed to 0 Delta NLS versus GFP105 but that the clearance of infectious virus is equivalent when the two groups are compared. Moreover, the 0 Delta NLS-infected mice displayed enhanced effector CD8(+) but not CD4(+) T cell responses from the draining lymph nodes at day 7 postinfection measured by gamma interferon (IFN-gamma) and tumor necrosis factor alpha production along with changes in cell metabolism. The increased effector function of CD8(+) T cells from 0 Delta NLS-infected mice was not driven by changes in antigen presentation but lost in the absence of a functional type I IFN pathway. These results are further supported by enhanced local expression of type I IFN and IFN-inducible genes along with increased IL-12 production by CD8 alpha(+) dendritic cells in the draining lymph nodes of 0 Delta NLS-infected mice compared to the GFP105-infected animals. It was also noted the recall to HSV-1 antigen by CD8(+) T cells was elevated in mice infected with HSV-1 0 Delta NLS compared to GFP105. Collectively, the results underscore the favorable qualities of HSV-1 0 Delta NLS as a candidate vaccine against HSV-1 infection. IMPORTANCE Cytotoxic T lymphocytes (CTLs) play a critical role in the clearance for many viral pathogens including herpes simplex virus 1 (HSV-1). Here, we compared the cellular innate and adaptive immune response in mice infected with an attenuated HSV-1 (0 Delta NLS) found to be a highly successful experimental prophylactic vaccine to parental HSV-1 virus. We found that CD8(+) T cell effector function is elevated in 0 Delta NLS-infected mice through noncognate signals, including interleukin-12 and type I interferon pathways along with changes in CD8(+) T cell metabolism, whereas other factors, including cell proliferation, costimulatory molecule expression, and antigen presentation, were dispensable. Thus, an increase in CTL activity established by exposure to HSV-1 0 Delta NLS in comparison to parental HSV-1 likely contributes to the efficacy of the vaccine and underscores the nature of the attenuated virus as a vaccine candidate for HSV-1 infection. Cytotoxic T lymphocytes (CTLs) play a critical role in the clearance for many viral pathogens including herpes simplex virus 1 (HSV-1). Here, we compared the cellular innate and adaptive immune response in mice infected with an attenuated HSV-1 (0 Delta NLS) found to be a highly successful experimental prophylactic vaccine to parental HSV-1 virus.