Adenoviral vector expressing ICP47 inhibits adenovirus-specific cytotoxic T lymphocytes in nonhuman primates.
Studies from several laboratories have shown that administration of E1-deleted Ad vectors results only in transient transgene expression in the lungs of immunocompetent animals. This is due, at least in part, to destruction of vector-transduced cells by host cellular immune responses (predominantly CD8(+) CTLs) directed against viral proteins and/or immunogenic transgene products. We have previously demonstrated that E1-deleted Ad vectors can lead to persistent expression of human cystic fibrosis transmembrane conductance regulator (hCFTR) in the lungs of several strains of immunocompetent mice, despite the presence of Ad-specific CTLs. However, we found that these same vectors gave rise only to transient hCFTR expression in the lungs of rhesus monkeys. We have constructed new Ad vectors that coexpress both hCFTR and the ICP47 gene from herpes simplex virus. ICP47 has been shown to inhibit the transporter associated with antigen presentation, thus blocking major histocompatibility antigen I (MHC class I)-mediated antigen presentation to CD8(+) T cells. The Ad/hCFTR/ICP47 vector decreased levels of cell-surface MHC class I molecules on infected monkey and human cell lines. Similar results were obtained with primary human cells and primary monkey airway epithelial cells. In vitro studies showed that the Ad/hCFTR/ICP47 vector decreased cytolysis by both monkey and human CTLs. When Ad/hCFTR/ICP47 was administered to the lungs of rhesus monkeys, it inhibited the generation of Ad-specific CTLs. However, natural killer cell activity was enhanced in monkeys treated with the Ad/hCFTR/ICP47 vector.
Scaria
A
A
Genzyme Corporation, 31 New York Avenue, Framingham, Massachusetts 01701, USA. Abraham.Scaria@genzyme.com
Sullivan
J A
JA
St George
J A
JA
Kaplan
J M
JM
Lukason
M J
MJ
Morris
J E
JE
Plog
M
M
Nicolette
C
C
Gregory
R J
RJ
Wadsworth
S C
SC
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D015870:Gene Expression; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000378:metabolism / Q000821:virology; D008253:Macaca mulatta; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019076:Transgenes; D014764:Viral Proteins
C505032:CFTR protein, human; D015395:Histocompatibility Antigens Class I; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D014764:Viral Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator