The aim of this application is to understand the mechanisms of induction of, and recognition by, antiviral cytotoxic T lymphocytes (CTL). CTL play a critical role in combating many virus infections (and in tumor surveillance), and molecular analysis of the CTL/target interaction will allow us to address several important questions. Firstly, how can viruses evade the CTL response to establish persistent infection (often with resultant disease)? Secondly, why is there a continued failure of the host to mount a CTL response to persistent infection, since virus protein is plentiful, i.e., how is persistence maintained? Thirdly, how successful is immunization in protecting against viruses which c an establish persistence by suppressing immune responses? fourthly, can the knowledge which accrues from these studies be used to design specific immunotherapy for treatment of persistent virus infection We are approaching these questions using as a model system lymphocytic choriomeningitis virus (LCMV) infection of its natural murine host. LCMV infection of an immunocompetent mouse induces a brisk CTL response with resultant virus clearance. LCMV genes, and sub-fragments thereof, have been expressed in vaccinia viruses. These recombinants have been used to identify LCMV target sites for CTL recognition and lysis, and have allowed us to demonstrate that small fragments of virus proteins are recognized (in association with host MHC) by CTL. These recombinant vaccinia are now being used to study the induction requirements for CTL, and their efficacy in protecting mice against both acute and persistent LCMV infection is under evaluation.
Our specific aims are, therefore: (1) to continue identification of virus epitopes on various MHC backgrounds; (2) to continue studies on CTL recognition of these epitopes; (3) to develop our analyses of CTL induction; (4) to assess the role of the various epitopes in protecting against subsequent LCMV challenge and (5) to develop a rational scheme to allow treatment of persistent virus infection by specific immunotherapy.
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