Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a “pan-herpesvirus” vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this.

Background Increased NK activation has been associated with resistance to HIV-1 infection in several cohorts of HIV-1 exposed, uninfected subjects. Inheritance of protective NK receptor alleles (KIR3DS1 and KIR3DL1high) has also been observed in a subset of HIV-1 exposed, uninfected subjects. However, the exact mechanism contributing to NK activation in HIV-1 exposed, uninfected intra-venous drug users (EU-IDU) remains to be elucidated. Objective We investigated the role of both host genotype and pathogen-induced dendritic cell modulation of NK activation during high-risk activity in a cohort of 15 EU-IDU subjects and 15 control, uninfected donors from Philadelphia. Design We assessed the activation status of NK cells and Dendritic cells by flow cytometry and utilized functional assays of NK-DC cross-talk to characterize the innate immune compartment in EU-IDU subjects. Results As previously reported, NK cell activation (CD69) and/or degranulation (CD107a) was significantly increased in EU-IDU subjects compared to control uninfected donors (p=0.0056, n=13). Genotypic analysis indicated that the frequency of protective KIR (KIR3DS1) and HLA-Bw4*80I ligands was not enriched in our cohort of EU-IDU subjects. Rather, plasmacytoid dendritic cells (PDC) from EU-IDU exhibited heightened maturation (CD83) compared to control uninfected donors (p=0.0011, n=12). When stimulated in vitro, both PDCs and NK cells from EU-IDU subjects maintained strong effector cell function and did not exhibit signs of exhaustion. Conclusion Increased maturation of PDCs is associated with heightened NK activation in EU-IDU subjects suggesting that both members of the innate compartment may contribute to resistance from HIV-1 infection in EU-IDU.