With greater than 1.6 million Americans infected annually (4), herpes simplex virus type 2 (HSV-2) is a sexually transmitted pathogen with a significant impact on public health. Typically, infection results in a lifelong latent infection of the host (15, 52). Causes for the success of HSV-2 in the human population include asymptomatic shedding of the virus even in the presence of CD8 ϩ cytotoxic T lymphocytes and the production of a viral glycoprotein that indirectly elicits NK cell death (8,44,51). There is also evidence to suggest that genital HSV-2 infection increases the susceptibility of individuals to other sexually transmitted diseases, including human immunodeficiency virus (6,20). Consequently, it is imperative to characterize the host response to infection and identify key components that contribute to virus resistance to devise a strategy that will significantly reduce viral prevalence.The development of a mouse model of genital HSV-2 infection (7, 40) has contributed to our understanding of the innate and adaptive immune response to infection. Specifically, the application of progesterone to mice prior to infection enhances susceptibility through the direct immunosuppressive action of the hormone and expression of a herpesvirus entry receptor, nectin 1 (20,25,34). In this rodent model, investigators have demonstrated the importance of the innate immune response, including neutrophils, NK cells, NKT cells, and the production of alpha/beta interferon (IFN-␣/), interleukin-12 (IL-12), IL-15, and IL-18 in suppressing HSV-2 replication and reducing virus-mediated mortality (5,13,16,30,36). Relative to the adaptive immune response, T and B cells are involved in controlling virus infection, although T cells appear to be more critical in this process (12,28,29,31,35,41). The contribution of IFN-␥ produced by CD4 ϩ T cells in reducing HSV-2 pathogenesis has been demonstrated using CD4-deficient mice and CD4 T cell, CD8 T cell, and IFN-␥ depletion studies (17,32,42). Such results are consistent with a supportive role in the development of a Th1 response (55) and a detrimental role in the development of a Th2 response (38) in the host following HSV-2 infection.Mobilization of T and B cells between the vaginal epithelium and the draining (iliac) lymph nodes during genital HSV-2 infection have been described previously (22). However, the role of chemokines in regulating this process is relatively unknown. CCR5 and CCR1 have been implicated in resistance to intraperitoneal infection, with HSV-2 impacting NK cell recruitment and activity at the site of infection (3, 49). Using a more conventional site of infection, RANTES/CCL5 (regulated on activation, normal T-cell expressed, and secreted) was found to reduce HSV-2-induced morbidity and mortality associated with an increase in IL-2 and IFN-␥ production in vaccinated mice when administered in the form of a DNA vaccine adjuvant (48). Since it has been reported that CCR5-deficient mice show a decrease in Th1 responses as measured by a decrease in IFN-␥ and IL-12 pro...