The T-cell-mediated resolution of herpes simplex virus type 2 (HSV-2) genital infections is not fully understood. In these studies, the mechanisms by which CD8 ؉ T cells clear virus from the genital epithelium were examined. Ovalbumin (OVA)-specific CD8 ؉ T cells from OT-I transgenic mice cleared a thymidine kinase-deficient, ovalbumin-expressing HSV-2 virus (HSV-2 tk ؊ OVA) from the genital epithelium of recipient mice, and clearance was abrogated by in vivo neutralization of gamma interferon (IFN-␥). Further, CD8؉ OT-I T cells deficient in IFN-␥ were unable to clear HSV-2 tk ؊ OVA from the vaginal epithelium. The requirement for cytolytic mechanisms in HSV-2 tk ؊ OVA clearance was tested in radiation chimeras by adoptive transfer of wild-type or perforin-deficient OT-I T cells to irradiated Fas-defective or wild-type recipients. Although a dramatic decrease in viral load was observed early after challenge with HSV-2 tk ؊ OVA, full resolution of the infection was not achieved in recipients lacking both perforin-and Fas-mediated cytolytic pathways. These results suggest that IFN-␥ was responsible for an early rapid decrease in HSV-2 virus titer. However, either perforin-or Fas-mediated cytolytic mechanisms were required to achieve complete clearance of HSV-2 from the genital epithelium.Herpes simplex virus type 2 (HSV-2) infects epithelial cells in the genital mucosa, spreads to the sensory ganglia via retrograde transport, and establishes a lifelong latent infection in sensory neurons (50). The virus periodically reactivates and descends sensory neurons via anterograde transport, resulting in development of recurrent lesions at or near the site of primary infection or in shedding of infectious virus in the absence of disease symptoms. The primary and recurrent lesions of immunocompetent individuals are generally self limiting and are resolved primarily by cell-mediated immune mechanisms. Recurrent disease is less well controlled in immunocompromised individuals, resulting in more frequent recurrences and sometimes severe mucocutaneous disease manifestations. Studies of HSV infection in human immunodeficiency virus (HIV)-infected individuals suggested that the severity of HSV disease could be inversely correlated with the number of HSV-specific CD8 ϩ T cells (39). Studies of recurrent HSV lesions in immunocompetent humans have demonstrated the early infiltration of CD4 ϩ T cells and macrophages, local production of IFN-␥, and late arrival of CD8ϩ T cells at the site of HSV infection. Both CD4 ϩ and CD8 ϩ T lymphocytes capable of IFN-␥ secretion and HSVspecific cytolysis have been isolated from human herpetic lesions (10) and clearance of infectious virus, and resolution of lesions has been correlated with the detection of HSV-specific cytolytic T-lymphocyte activity (10, 22-23). However, the role for these cytolytic and noncytolytic immune mechanisms in resolution of HSV-2 genital infections is not well understood.Murine models of HSV-2 genital infection have also demonstrated the importance of cell-mediated imm...

In primary infection, CD8؉ T cells are important for clearance of infectious herpes simplex virus (HSV) from sensory ganglia. In this study, evidence of CD4 ؉ T-cell-mediated clearance of infectious HSV type 1 (HSV-1) from neural tissues was also detected. In immunocompetent mice, HSV-specific CD4 ؉ T cells were present in sensory ganglia and spinal cords coincident with HSV-1 clearance from these sites and remained detectable at least 8 months postinfection. Neural CD4 ؉ T cells isolated at the peak of neural infection secreted gamma interferon, tumor necrosis factor alpha, interleukin-2 (IL-2), or IL-4 after stimulation with HSV antigen. HSV-1 titers in neural tissues were greatly reduced over time in CD8؉ T-cell-deficient and CD8

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Intravaginal (ivag) or intranasal (i.n.) immunization of C57BL/6J (B6) mice with a thymidine kinase-deficient strain (tk-) of herpes simplex virus type 2 (HSV-2) resulted in comparable protection of the genital epithelium and sensory ganglia against HSV-2 challenge. In contrast, protection of these sites was much reduced in i.n.-immunized compared to ivag-immunized B cell-deficient microMT mice. Fewer HSV-specific T cells were detected in the genital epithelium of i.n.-immunized compared to ivag-immunized microMT mice after HSV-2 challenge. Passive transfer of HSV-specific serum to immune microMT mice restored protection of these sites against HSV-2 challenge. These results suggest that protection of genital and neuronal sites may be conferred by i.n. immunization but may be more dependent on antibody-dependent mechanisms than the protection resulting from genital immunization. These results have implications for immunization strategies to elicit high levels of cell-mediated protection of the genital tract and sensory ganglia.

Interferon gamma (IFNγ) is important for immune resistance to herpes simplex virus (HSV) infection. To examine the influence of IFNγ on the development of HSV-specific immune responses and test for IFNγ-independent adaptive immune mechanisms of protection, IFNγ-deficient mice (IFNγ−/−) were immunized with thymidine kinase-deficient HSV-2 (HSV-2 333tk−). HSV-specific cellular and humoral responses were elicited in immunized IFNγ−/− mice resulting in increased resistance relative to non-immune C57BL/6J (B6) mice following challenge with fully virulent HSV-2. CD8+ T cells from IFNγ−/− mice displayed cytotoxic activity and secreted TNFα. HSV-specific CD4+ T cells from immunized IFNγ−/− mice secreted IL-4, TNFα, and IL-17, but unlike T cells from HSV-immune B6 mice, could not clear virus from genital tissue following adoptive transfer. HSV-immune IFNγ−/− mice produced predominantly IgG1 HSV-specific antibodies while immune B6 mice produced predominantly IgG2c antibodies. Transfer of equivalent amounts of HSV-specific antibodies from either strain to naïve mice imparted equivalent early resistance against infection of the genital epithelia. However, protection against neurological symptoms mediated by immune B6 antibodies was superior late in infection. Taken together, these results demonstrate that the limited resistance of HSV-immune IFNγ−/− mice to HSV-2 infection resulted from the action of HSV-specific Ab rather than IFNγ-independent effector functions of T cells. Further, protection against neurological manifestations of HSV-2 infection was superior in mice receiving Ab from immune B6 mice suggesting that Ab-mediated protective mechanisms involving IFNγ-induced IgG subclasses were more effective once virus had spread to neural tissues.