Adenoviral vector expressing ICP47 inhibits adenovirus-specific cytotoxic T lymphocytes in nonhuman primates

Studies from several laboratories have shown that administration of E1-dele ted Ad vectors results only in transient transgene expression in the lungs of immunocompetent animals. This is due, at least in part, to destruction o f vector-transduced cells by host cellular immune responses (predominantly CD8(+) CTLs) directed against viral proteins and/or immunogenic transgene p roducts. We have previously demonstrated that E1-deleted Ad vectors can lea d to persistent expression of human cystic fibrosis transmembrane conductan ce regulator (hCFTR) in the lungs of several strains of immunocompetent mic e, despite the presence of Ad-specific CTLs. However, we found that these s ame vectors gave rise only to transient hCFTR expression in the lungs of rh esus monkeys. We have constructed new Ad vectors that coexpress both hCFTR and the ICP47 gene from herpes simplex virus. ICP47 has been shown to inhib it the transporter associated with antigen presentation, thus blocking majo r histocompatibility antigen I (MHC class I)-mediated antigen presentation to CD8(+) T cells. The Ad/hCFTR/ICP47 vector decreased levels of cell-surfa ce MHC class I molecules on infected monkey and human cell lines. Similar r esults were obtained with primary human cells and primary monkey airway epi thelial cells. In vitro studies showed that the Ad/hCFTR/ICP47 vector decre ased cytolysis by both monkey and human CTLs. When Ad/hCFTR/ICP47 was admin istered to the lungs of rhesus monkeys, it inhibited the generation of Ad-s pecific CTLs. However, natural killer cell activity was enhanced in monkeys treated with the Ad/hCFTR/ICP47 vector.