T lymphocytes are the main mediators of the protective immune response in recurrent herpes simplex. Early in the development of recurrent lesions, macrophages and CD4 T lymphocytes predominate in the mononuclear infiltrate surrounding infected epidermal cells. Human epidermal keratinocytes allow herpes simplex virus type 1 (HSV-1) replication and human leukocyte antigen (HLA)-DR is strongly expressed in vivo. In vitro, their pretreatment with IFN-gamma induced HLA-DR expression and partially reversed major histocompatibility complex class I down-regulation by the virus. Mononuclear cell cytotoxicity for these cells was mediated predominantly by CD4 and also by CD8 T cells. Late HSV-1 proteins were the major targets for CD4 CTL, while CD8 CTL predominantly targeted early HSV-1 proteins. Here it is shown that both mononuclear and CD4 CTL consistently recognized the major HSV-1 glycoproteins, gB, gC, gD and gH, using IFN-gamma-pretreated keratinocytes infected with vaccinia virus-HSV glycoprotein recombinants (VvgB, VvgC, VvgD or VvgH). CD4 cytotoxicity was highest for VvgD-infected keratinocytes, followed by VvgB or VvgC and then VvgH in seven patients. CD4 CTL from two of 13 patients also recognized an epitope in the HSV tegument protein VP16, demonstrated by comparing cytotoxicity for the partial deletion mutants RP3 or RP4 and the parental RP1 HSV strain. In summary, the major HSV glycoproteins gB, gC and gD were consistently the major targets for CD4 CTL in VvgB-, VvgC-, VvgD- and VvgH-infected, IFN-gamma-pretreated human epidermal keratinocytes in vitro.


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