Herpes simplex viruses (HSV) are highly pervasive pathogens in the human host with a seroconversion rate upwards of 60% worldwide. HSV type 1 (HSV-1) is associated with the disease, herpetic stromal keratitis, the leading cause of infectious corneal blindness in the industrialized world. Individuals suffering from genital herpes associated with HSV type 2 (HSV-2) are found to be two to three fold more susceptible in acquiring human immunodeficiency virus (HIV). The morbidity associated with these infections is principally due to the inflammatory response, the development of lesions, and scarring. Chemokines have become an important aspect in understanding the host immune response to microbial pathogens due in part to the timing of expression. In this paper, we will explore the current understanding of chemokine production as it relates to the orchestration of the immune response to HSV infection.

We investigated the mechanism of resistance to genital herpes simplex virus type 2 (HSV-2) infection in mice transfected with the murine alpha-1 interferon (IFN-␣1) transgene. In situ transfection of mice with the IFN-␣1 transgene resulted in an elevation in an IFN-responsive gene, RNA-dependent protein kinase (PKR), but not 2,5-oligoadenylate synthetases (OAS), in vaginal tissue. Coupled with the finding that mice lacking a functional PKR pathway were no longer resistant to genital HSV-2 infection following transfection with the IFN-␣1 transgene in comparison to wild-type mice or mice lacking a functional OAS pathway, these results suggest that PKR is the dominant antiviral pathway activated by the IFN-␣1 transgene.

Summary Mice deficient in RNA‐dependent protein kinase (PKR–/–) or deficient in PKR and a functional 2′,5′‐oligoadenylate synthetase (OAS) pathway (PKR/RL–/–) are more susceptible to genital herpes simplex virus type 2 (HSV‐2) infection than wild‐type mice or mice that are deficient only in a functional OAS pathway (RL–/–) as measured by survival over 30 days. The increase in susceptibility correlated with an increase in virus titre recovered from vaginal tissue or brainstem of infected mice during acute infection. There was also an increase in CD45+ cells and CD8+ T cells residing in the central nervous system of HSV‐2‐infected PKR/RL–/– mice in comparison with RL–/– or wild‐type control animals. In contrast, there was a reduction in the HSV‐specific CD8+ T cells within the draining lymph node of the PKR/RL–/– mice. Collectively, activation of PKR, but not of OAS, contributes significantly to the local control and spread of HSV‐2 following genital infection.