PREEXISTING HERPES-SIMPLEX VIRUS-1 (HSV-1) IMMUNITY DECREASES, BUT DOES NOT ABOLISH, GENE-TRANSFER TO EXPERIMENTAL BRAIN-TUMORS BY A HSV-1 VECTOR

The influence of pre-existing anti-herpes simplex type 1 (HSV-1) immun ity on HSV-1-vector-mediated gene transfer to glioma cells was analyze d in this gene marking study using intracranial D74 gliomas in syngene ic Fischer rats. The HSV-1 mutant virus used, hrR3, is defective in ri bonucleotide reductase and bears the marker genes E. coli lacZ and HSV -1 thymidine kinase (HSVtk). Initial marker gene expression in tumors 12 h after direct virus injection was reduced in immunized animals to about 15% of that in non-immunized animals. Marker gene expression in both sets stayed at initial levels for 2 days after intratumoral injec tion and declined markedly on day 5. Inflammatory infiltrates in the t umor were more prominent in HSV-1-immunized, as compared with nonimmun ized animals, at 12 and 24 h, but appeared similar at 2-5 days after i njection. By day 10, the immune reaction had subsided in immunized ani mals and macrophages remained only in nonimmunized animals. In conclus ion, gene transfer to brain tumors using a HSV-1 vector was greatly re duced, but not competely abolished, under pre-immunization conditions. Pre-existing antibodies to HSV-1 may also serve a positive role in pr oviding an increased margin of safety in intracranial application of H SV-1 vectors by limiting spread of the virus within the brain and to o ther tissues.