Mouse adenovirus type 1 and human adenovirus type 5 differ in endothelial cell tropism and liver targeting.
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.
Lenaerts
Liesbeth
L
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
McVey
John H
JH
Baker
Andrew H
AH
Denby
Laura
L
Nicklin
Stuart
S
Verbeken
Erik
E
Naesens
Lieve
L
D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000260:Adenoviruses, Human / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D005170:Factor X / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000821:virology*; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D018523:Tropism
D011509:Proteoglycans; D011991:Receptors, Virus; D005170:Factor X