CELLULAR IMMUNE-RESPONSE TO ADENOVIRAL VECTOR INFECTED-CELLS DOES NOTREQUIRE DE-NOVO VIRAL GENE-EXPRESSION - IMPLICATIONS FOR GENE-THERAPY

Replication-defective adenoviral (RDAd) vectors can be generated at hi gh titers and infect both dividing and nondividing cells. Long term ex pression in the transduced tissue, however, has been a problem because of the cellular immune responses against the infected cells. We demon strate that mice injected with RDAd vectors containing mouse leptin ge ne reduce food intake and lose weight for only 7 to 10 days. Splenocyt es obtained from infected mice are able to lyse target cells infected with RDAd vectors. Surprisingly, target cells infected with psoralen-t reated, UV-crosslinked, biologically inactive RDAd also were lysed eff iciently by the effector cells, Furthermore, splenocytes obtained from mice injected with inactive RDAd vectors efficiently lysed target cel ls infected with RDAd vectors, Whether RDAd vectors were injected i.m. or i.v, or through an i.p. route, the extent of lysis was similar. We propose that cel:ls infected with RDAd vectors present antigens for r ecognition by class 1 major histocompatibility complex-restricted cyto toxic T lymphocytes by a mechanism that does not require viral replica tion or de novo protein synthesis, These results should prompt reevalu ation of the use of RDAd vectors for gene therapy when long-term expre ssion is required.