Arena-viruses are rodent-borne pathogens that cause significant morbidity and mortality in humans. Pathogenic arenaviruses include Lassa (LASV), lymphocytic choriomeningitis (LCMV), Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV) and Whitewater Arroyo (WWAV) viruses. Following human infection with the Old World arenaviruses LCMV or LASV, cellular immunity plays a pivotal role in viral clearance and protective immunity. Therefore, it is important that sensitive reagents to measure the cellmediated immune response in the context of human infection or in response to vaccine candidates are developed. The identification of HLA-restricted epitopes is required to develop assays that can be used to determine the quality of immune responses, define correlates of protection and immunopathology, and ultimately guide the selection of candidate vaccines. In order to identify human CD8+ T cell epitopes from pathogens, we have established an approach that utilizes bioinformatic predictions to identify candidate epitopes, in vitro MHC binding assays and in vivo immunogenicity studies in HLA transgenic mice to validate epitopes, and vaccination studies to evaluate whether epitopes are protective against viral challenge. Over the few past years, we used this approach to identify the first human CD8+ T cell epitopes from LCMV (1,2,3). In subsequent studies we have shown that immunization of HLA-A2 transgenic mice with one of these epitopes, GPC[447,455] led to significant reductions in viral titer following challenge with LCMV and protected animals from lethal disease.
Available options for Vaccines and antivirals effective against arenaviruses are extremely limited. This project proposes to refine the development and delivery of broad spectrum vaccines against the pathogenic arenaviruses of the Old World and New World. We propose also to expand on our findings that drugs targeted at the common conserved termini of the arenavirus genome are effective antivirals. These studies will bring us closer to the goal of viable antivirals and vaccines against arenaviruses.
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