INSERTION OF THE ADENOVIRAL E3 REGION INTO A RECOMBINANT VIRAL VECTORPREVENTS ANTIVIRAL HUMORAL AND CELLULAR IMMUNE-RESPONSES AND PERMITS LONG-TERM GENE-EXPRESSION

Recombinant adenoviruses (Ads) are highly efficient at transferring fo reign genes to the liver in vivo; however, the duration of gene expres sion is limited by the host antiviral immune response, which prevents expression upon readministration of the virus, To test whether overexp ression of the immunomodulatory products of the early Ad genome region 3 (E3) could prevent the antiviral immune response and prolong expres sion of foreign genes delivered by Ad vectors, we injected a recombina nt Ad (Ad-E3-hBUGT), containing both E3 and the human idine-diphosphog lucuronate-glucuronosyltransferase (BUGT) genes, into BUGT-deficient h yperbilirubinemic Gunn rats, Control Gunn rats received Ad-hBUGT, whic h expresses human BUGT alone, An initial injection of either virus res ulted in hepatic expression of human BUGT as evidenced by excretion of bilirubin glucuronides in bile and a reduction of mean serum bilirubi n levels from 7.0 mg/dl to 1.9-2.7 mg/dl within 7 days, In Ad-E3-hBUGT -injected rats, serum bilirubin levels increased to 4.5 mg/dl by 84 da ys after infection, but a second administration of the virus on that d ay resulted in a hypobilirubinemic response similar to that seen with the first injection, In contrast, rats receiving Ad-hBUGT had serum bi lirubin levels of 7 mg/dl on day 84 after infection, but showed no red uction of serum bilirubin by reinjection of the virus on that day, In the rats injected with Ad-E3-hBUGT, but not in the ones injected with Ad-hBUGT, there was a marked inhibition of the antiviral antibody and Ad specific cytotoxic T lymphocyte responses, This is the first demons tration that insertion of E3 genes in recombinant Ads facilitates read ministration of a functional vector for long-term correction of an inh erited metabolic disorder.