Immune responses to adenovirus and adeno-associated virus in humans.
Vectors based on human adenovirus (Ad) and adeno-associated virus (AAV) are being evaluated for human gene therapy. The response of the host to the vector, in terms of antigen-specific immunity, will play a substantial role in clinical outcome. We have surveyed cohorts of normal subjects and cystic fibrosis patients for pre-existing immunity to these viruses, caused by naturally acquired infections. A number of humoral and cellular assays to adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 2 (AAV2) were performed from serum and peripheral blood mononuclear cells. Virtually all subjects had Ig to Ad5 although only 55% of these antibodies neutralized virus (NAB). Approximately two of three patients demonstrated CD4+ T cells that proliferated to Ad antigens of which most were of the TH1 subset, based on cytokine secretion. A substantially different pattern of immune responses was observed to AAV2. Although virtually all patients had Ig to AAV2, most of these antibodies were not neutralizing (32% NAB) and only 5% of patients had peripheral blood lymphocytes that proliferated in response to AAV2 antigens. These studies demonstrate marked heterogeneity in pre-existing immunity to Ad5 and AAV2 in human populations. The impact of these findings on outcome following gene therapy will require further study.
Chirmule
N
N
Institute for Human Gene Therapy and Departments of Molecular and Cellular Engineering, and Medicine, University of Pennsylvania, Philadelphia, PA 19104-6100, USA.
Propert
K
K
Magosin
S
S
Qian
Y
Y
Qian
R
R
Wilson
J
J
D000256:Adenoviridae / Q000276:immunology*; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D003550:Cystic Fibrosis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D000229:Dependovirus / Q000276:immunology*; D005260:Female; D005822:Genetic Vectors / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology
D000914:Antibodies, Viral; D016207:Cytokines; D007074:Immunoglobulin G