Inflammatory effects of gene transfer into the CNS with defective HSV-1 vectors.
The use of viral vectors which infect and express genes in post-mitotic neurons is a potential strategy for the treatment of disorders affecting the central nervous system (CNS). However, the inflammatory consequences of such strategies have yet to be systematically examined. Preparations of non-replicating defective herpes simplex virus type 1 (HSV-1) amplicon vectors containing the lacZ gene were obtained by standard methods and stereotaxically injected into the adult rat dentate gyrus (DG). The consequent gene expression and inflammatory effects following microinjection were investigated. beta-Galactosidase activity was detected in neurons of the DG from 24 h to at least 12 days after vector injection. A strong inflammatory response developed within 2 days, characterized by diffuse up-regulation of major histocompatibility complex (MHC) class I antigens and the activation of microglia. After 4 days the recruitment of MHC class II+ cells, activated T lymphocytes and macrophages was detected. These features persisted for at least 31 days. Of importance was the finding of beta-galactosidase activity in a bilateral group of neurons in the supramammillary nuclei (SMN) of the posterior hypothalamus, known to send afferent projections to the DG. The onset of inflammation at this secondary site was delayed, but its cellular characteristics resembled those found at the primary site of injection. Thus, the use of preparations of defective HSV-1 vectors for gene transfer in the CNS has immunological implications both at primary and secondary sites within the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)
Wood
M J
MJ
Department of Neurobiology and Behavior, Rockefeller University, New York 10021, USA.
Byrnes
A P
AP
Pfaff
D W
DW
Rabkin
S D
SD
Charlton
H M
HM
D000818:Animals; D003673:Defective Viruses / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D018891:Dentate Gyrus / Q000201:enzymology / Q000473:pathology; D004660:Encephalitis / Q000209:etiology* / Q000473:pathology; D015870:Gene Expression; D018014:Gene Transfer Techniques / Q000009:adverse effects*; D015316:Genetic Therapy / Q000009:adverse effects; D005822:Genetic Vectors / Q000009:adverse effects*; D018259:Herpesvirus 1, Human / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity; D007763:Lac Operon; D051381:Rats; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics
D001616:beta-Galactosidase