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Mouse adenovirus type 1 and human adenovirus type 5 differ in endothelial cell tropism and liver targeting
Author(s) -
Lenaerts Liesbeth,
McVey John H.,
Baker Andrew H.,
Denby Laura,
Nicklin Stuart,
Verbeken Erik,
Naesens Lieve
Publication year - 2009
Publication title -
the journal of gene medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.689
H-Index - 91
eISSN - 1521-2254
pISSN - 1099-498X
DOI - 10.1002/jgm.1283
Subject(s) - tropism , tissue tropism , adenovirus infection , adenoviridae , biology , viral vector , cell culture , cell type , cell , virology , mastadenovirus , factor ix , recombinant dna , microbiology and biotechnology , virus , biochemistry , genetics , gene
Background For adenovirus vectors derived from human serotype 5 (Ad5), the efficiency and safety after intravascular delivery is hindered by their sequestration in nontarget tissues, predominantly the liver. The latter is largely dictated by adenovirus binding to blood coagulation zymogens. In addition, several target cells, such as endothelial and smooth muscle cells, are difficult to transduce by Ad5 due to the low expression of the primary coxsackie‐adenovirus receptor (CAR). Therefore, alternative adenovirus serotypes are being explored. Methods In the present study, we assessed the tropism of mouse adenovirus type 1 (MAV‐1), a nonhuman adenovirus for which cellular attachment is CAR‐independent. Results The typical replication of MAV‐1 in endothelial cells as observed in vivo was not reflected in elevated attachment to primary and continuous endothelial cells in cell culture. Remarkably, MAV‐1 displayed a higher affinity for primary human smooth muscle cells than recombinant Ad5 (rAd5). Attachment of MAV‐1 to human and mouse cells of hepatocyte origin was not altered by physiological concentrations of human coagulation factor XI (FXI) or the vitamin K‐dependent FIX, FX and FVII. By contrast, attachment of Ad5‐derived vectors was enhanced at least eight‐fold by FX. Using surface plasmon resonance, MAV‐1 was shown to directly associate with human FX and murine FX and FIX but, opposite to rAd5, this interaction did not lead to enhanced cellular attachment. In intravenously injected severe combined immunodeficiency mice, distribution of MAV‐1 to the liver was markedly lower than that observed with rAd5. Conclusions Our data on the tropism of MAV‐1 suggest that this virus may find utility in the field of gene therapy. Copyright © 2008 John Wiley & Sons, Ltd.