Vaccination Against Pathogens Targeting Cell-Derived Cryptic Antigens

CD8+ T-cell responses are an important component of a protective immune response in many pathogenic infections, including HIV and Herpesviridae such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Identification of pathogen-encoded protective antigens, antigenic heterogeneity, and progressive immune dysfunction are major barriers facing the development of effective CD8+ T-cell-targeted vaccines. Here we tested the hypothesis that pathogen-infected cells can be sensitized to vaccination against host-derived antigens presented by the infected cells with reduced expression of TAP (transporter associated with antigen processing). In this study, we show the following: first, natural or targeted downregulation of TAP in CMV- and EBV- or HIV-infected cells, respectively, leads to the presentation of a cell-encoded nonmutated cryptic epitope, initially described in tumor cells with reduced TAP expression; second, peripheral blood mononuclear cell-derived CD8+ T cells enriched for multiple TAP downregulation-induced epitopes recognize TAPlow CMV-, EBV-, and HIV-infected cells, leading to the depletion of TAPlow-infected cells and the expression of activation markers in the T cells. This study describes a prototype of a universal drug formulation to vaccinate against tumors and pathogen-infected cells, dispensing with the need to identify pathogen- or tumor-specific antigenic targets and obviating the limitations associated with antigenic heterogeneity and immune dysfunction characteristic of pathogens such as HIV.