IMMUNOLOGICAL INSTABILITY OF PERSISTENT ADENOVIRUS VECTORS IN THE BRAIN - PERIPHERAL EXPOSURE TO VECTOR LEADS TO RENEWED INFLAMMATION, REDUCED GENE-EXPRESSION, AND DEMYELINATION

Nonreplicating adenovirus vectors are being developed as vehicles for the delivery of therapeutic genes in vivo. Whereas in many organs an a ntiviral T cell response eliminates the vector and damages local tissu e, when adenovirus vectors are injected into the brain the subsequent immune attack can be ineffective, allowing the vector to persist. In t he present study, E1-deleted human adenovirus vectors were injected in to the caudate nucleus of rats. Two months later, expression of protei n from the vector was still evident and little inflammation was seen. A subcutaneous injection of adenovirus vector at this time, however, l ed within 2 weeks to severe mononuclear inflammation and microglial ac tivation in the caudate. This caused local demyelination and a decreas e in detectable protein expression from the vector. Interestingly, int ense microglial activation and numerous lymphocytes and monocytes were also seen in brain areas containing neurons capable of retrogradely t ransporting the adenovirus vector from the caudate. Control experiment s established that this inflammation in distant brain areas was not a nonspecific consequence of degeneration. These experiments demonstrate that although adenovirus vectors can persist in the brain without cau sing chronic inflammation, they remain the potential target of a damag ing cell-mediated immune response brought about by a subsequent periph eral exposure to vector. The finding of lymphocytes in brain areas tha t project to the caudate further shows that viral antigens that are re trogradely transported by neurons can also be the target of a T cell a ttack.