Viral Immunology

Our Research Proposal is widely aimed at improving the control of chronic infections by the immune system. For these pathologies, the cellular immune response, as opposed to antibodies alone, plays a leading role. Although there is an impressive body of knowledge, vaccines inducing a potent and long-lasting T-cell immunity are still not available. Some chronic infections and some tumors escape immune control by interfering with recognition by CD8 cytotoxic T lymphocytes, for example, by interfering with TAP transporter. Our Proposal is aimed first at studying the molecular mechanisms and rules that lead to antigen processing and presentation in the absence of the TAP transporter. TAP is frequently targeted by viruses and very often by tumors, contributing to virulence and aggressiveness of both pathologies. TAP transporter is a key player in the antigen processing and presentation pathway that shuttles viral or altered peptides into the endoplasmic reticulum, so that major histocompatibility complex class I molecules, MHC I, can present them at the cell surface for recognition and elimination of infected or tumor cells by CD8 cytotoxic T lymphocytes. When TAP is inhibited, many peptides cannot be presented and immunosurveillance is compromised.

We work with TAP-independent peptides derived from vaccinia virus, VACV, and will a) study their common molecular features by bioinformatic, biochemical and genetic approaches; b) inquire into the mechanisms by which they traverse different membranes in uninfected and in infected cells, by exploring calmodulin and TRC40-mediated routes of alternative transport of small proteins into the endoplasmic reticulum; and c) evaluate their protective capacity in vivo in the absence of TAP.