Adenovirus type 5 interactions with human blood cells may compromise systemic delivery.
Intravenous delivery of adenovirus vectors requires that the virus is not inactivated in the bloodstream. Serum neutralizing activity is well documented, but we show here that type 5 adenovirus also interacts with human blood cells. Over 90% of a typical virus dose binds to human (but not murine) erythrocytes ex vivo, and samples from a patient administered adenovirus in a clinical trial showed that over 98% of viral DNA in the blood was cell associated. In contrast, nearly all viral genomes in the murine bloodstream are free in the plasma. Adenovirus bound to human blood cells fails to infect A549 lung carcinoma cells, although dilution to below 1.7 x 10(7) blood cells/ml relieves this inhibition. Addition of blood cells can prevent infection by adenovirus that has been prebound to A549 cells. Adenovirus also associates with human neutrophils and monocytes ex vivo, particularly in the presence of autologous plasma, giving dose-dependent transgene expression in CD14-positive monocytes. Finally, although plasma with a high neutralizing titer (defined on A549 cells) inhibits monocyte infection, weakly neutralizing plasma can actually enhance monocyte transduction. This may increase antigen presentation following intravenous injection, while blood cell binding may both decrease access of the virus to extravascular targets and inhibit infection of cells to which the virus does gain access.
Department of Clinical Pharmacology, University of Oxford, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.
Mark
M
Lyons
David
D
Onion
Nicky K
NK
Green
Kriss
K
Aslan
Ratna
R
Rajaratnam
Miriam
M
Bazan-Peregrino
Sue
S
Phipps
Sarah
S
Hale
Vivien
V
Mautner
Leonard W
LW
Seymour
Kerry D
KD
Fisher
D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods* / Q000592:standards; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D015203:Reproducibility of Results