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Monophosphoryl Lipid A and QS21 Increase CD8 T Lymphocyte Cytotoxicity to Herpes Simplex Virus-2 Infected Cell Proteins 4 and 27 Through IFN- and IL-12 Production¹

Zorka Mikloska^2,*, Monica Rückholdt^*, Iraj Ghadiminejad, Heather Dunckley, Martine Denis^§ and Anthony L. Cunningham^*

^* Centre for Virus Research, Westmead Millennium Institute, Westmead Hospital and University of Sydney, Westmead, Australia; Centre for Kidney Research, New Children’s Hospital, Sydney, Australia; Australian Red Cross Blood Service Tissue Typing Department, Molecular Genetics Laboratory, Sydney, Australia; and ^§ SmithKline Beecham Biologicals, Rixensart, Belgium

We have shown previously that IFN- pretreatment of human epidermal cells (ECs) cultured in vitro partially reverses down-regulation of surface MHC class I by HSV infection, allowing recognition by CD8 CTLs, and that HSV immediate early (IE)/early (E) proteins are the predominant targets for CD8 CTLs. In this study of 25 subjects, CD8 CTLs recognized the HSV-2 IE infected cell protein 27 (ICP27) (expressed in autologous IFN--pretreated, Vaccinia virus recombinant-infected ECs) in all subjects studied, ICP4 in 89%, and ICP0 in 11%. The main hierarchy of recognition was ICP27 > ICP4. ICP27 was the dominant target in 89% of subjects but showed great individual variability in the degree of cytotoxicity. CD8 cytotoxicity specific for HSV-2 IE proteins was enhanced by 48–67% when CD8 CTLs were coincubated with the combination of monophosphoryl lipid A and QS21 adjuvants at the time of Ag presentation. These adjuvants also significantly enhanced IL-12 and IFN- production from nonadherent mononuclear cells stimulated by HSV-2-infected ECs. Addition of IL-12 and IFN- at the time of initial Ag presentation enhanced CD8 cytotoxicity to levels comparable with those stimulated by the adjuvants. Addition of neutralizing Abs to IL-12 or IFN- inhibited CD8 T cell cytotoxicity up to 95% when a combination of the Abs were added at the time of initial Ag presentation. Therefore, the mechanism for the enhancement of CD8 T cell cytotoxicity by adjuvants in this system appears to be via increased levels of IL-12 and IFN-.

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