Induction of immunity to antigens expressed by recombinant adeno-associated virus depends on the route of administration

Recombinant adeno-associated virus (rAAV) is a replication-defective parvov irus which is being explored as a vector for gene therapy because of its br oad host range, excellent safety profile, and durable transgene expression in infected hosts. rAAV has also been reported by several groups to induce little or no immune response to its encoded transgene products. In this stu dy Re examined the immunogenicity of rAAV by studying the immune response o f C57BL/6 mice to a single dose of rAAV-encoding ovalbumin (AAV-Ova) admini stered by a variety of routes. Mice injected with AAV-Ova intraperitoneally (ip), intravenously, or subcutaneously developed potent ovalbumin-specific cytotoxic T lymphocytes (CTL) as well as anti-ovalbumin antibodies and ant ibodies to AAV, In contrast, mice injected with AAV-Ova intramuscularly dev eloped a humoral response to the virus and the transgene but minimal ovalbu min-specific CTLs. The induced CTL response after ip administration of AAV- Ova protected mice against a subsequent tumor challenge with an ovalbumin-t ransfected B16 melanoma cell line. Studies of the mechanism by which AAV-Ov a induces CTL confirmed that the virus; delivers the transgene product into the classical MHC class I pathway of antigen processing. Mice that previou sly had been exposed to rAAV vectors failed to develop ovalbumin-specific C TL following administration of AAV-Ova, Analysis of these mice revealed the presence of circulating anti-AAV antibodies that blocked rAAV transduction in vitro and inhibited CTL induction in vivo, These results suggest a poss ible role for rAAV in the immunotherapy of malignancies and viral infection s, although induced antibody responses to AAV may limit its ability to be a dministered for repeated vaccinations. (C) 1999 Academic Press.