Previous studies by our group identified a highly efficacious vaccine 0ΔNLS (deficient in the nuclear localization signal of infected cell protein 0) against 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 0ΔNLS versus the parental, GFP105. The results show that local viral infection and replication are controlled more efficiently in mice exposed to 0ΔNLS versus GFP105 but clearance of infectious virus is equivalent comparing the two groups. Moreover, the 0ΔNLS-infected mice displayed enhanced effector CD8
+
but not CD4
+
T cell responses from the draining lymph nodes at day 7 post infection measured by IFN-γ and TNF-α production along with changes in cell metabolism. The increased effector function of CD8
+
T cells from 0ΔNLS-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 CD8α
+
DCs in the draining lymph nodes of 0ΔNLS-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 0ΔNLS compared to GFP105. Collectively, the results underscore the favorable qualities of HSV-1 0ΔNLS 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 (0ΔNLS) 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 0ΔNLS-infected mice through noncognate signals including IL-12 and type I interferon (IFN) pathways along with changes in CD8
+
T cell metabolism whereas other factors including cell proliferation, co-stimulatory molecule expression and antigen presentation were dispensable. Thus, an increase in CTL activity established by exposure to HSV-1 0ΔNLS 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.
