Presentation of HSV antigens and lipopeptides to T cells

Abstract

Currently there is no effective vaccine for genital and neonatal herpes. The most efficacious vaccine candidates in clinical trials to date failed to induce protective CD8+ T cell immunity and yet CD4+ and CD8+ T cells play a major role in controlling HSV mucocutaneous infection in humans. This thesis aimed at defining immunodominant CD8+ T cell epitopes from Herpes simplex virus type 2 (HSV2) and to combine these with T helper cell epitopes and the TLR2 agonist, Pam2Cys, as self-adjuvanted lipopeptides for use as possible HSV vaccine candidates. An ICP8 peptide ‘9’ was identified by predictive algorithms, and when conjugated, directly stimulated CD8+ T cell interferon gamma responses in some HLA-A2 donors. However a Pam2Cys conjugated 12 mer, peptide in gD ’30.5’, previously defined to stimulate CD4+ T cell interferon gamma responses, consistently and much more markedly stimulated CD8+ T cell responses and was restricted to HLA-A*02:01 and HLA-B*44:02. Furthermore it synergistically enhanced the total T cell response when CD4+ and CD8+ T cells were co-cultured compared CD4+ and CD8+ T cells alone. Pam2Cys-gD2 peptide 30.5 presentation to CD4+ T cells but not CD8+ T cells required endosomal acidification whereas CD8+ T cell stimulation required proteasomal processing, defining a cross presentation pathway. All the lipopeptides induced MDDC maturation, upregulating the maturation markers CD80 and CD83. Pam2Cys-gD-30.5 was therefore identified as a potential HSV vaccine candidate and is capable of eliciting a strong human CD4+ and CD8+ T cell responses.