The cell adhesion molecule "CAR" and sialic acid on human erythrocytes influence adenovirus in vivo biodistribution.
Although it has been known for 50 years that adenoviruses (Ads) interact with erythrocytes ex vivo, the molecular and structural basis for this interaction, which has been serendipitously exploited for diagnostic tests, is unknown. In this study, we characterized the interaction between erythrocytes and unrelated Ad serotypes, human 5 (HAd5) and 37 (HAd37), and canine 2 (CAV-2). While these serotypes agglutinate human erythrocytes, they use different receptors, have different tropisms and/or infect different species. Using molecular, biochemical, structural and transgenic animal-based analyses, we found that the primary erythrocyte interaction domain for HAd37 is its sialic acid binding site, while CAV-2 binding depends on at least three factors: electrostatic interactions, sialic acid binding and, unexpectedly, binding to the coxsackievirus and adenovirus receptor (CAR) on human erythrocytes. We show that the presence of CAR on erythrocytes leads to prolonged in vivo blood half-life and significantly reduced liver infection when a CAR-tropic Ad is injected intravenously. This study provides i) a molecular and structural rationale for Ad-erythrocyte interactions, ii) a basis to improve vector-mediated gene transfer and iii) a mechanism that may explain the biodistribution and pathogenic inconsistencies found between human and animal models.
Seiradake
Elena
E
European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France.
Henaff
Daniel
D
Wodrich
Harald
H
Billet
Olivier
O
Perreau
Matthieu
M
Hippert
Claire
C
Mennechet
Franck
F
Schoehn
Guy
G
Lortat-Jacob
Hugues
H
Dreja
Hanna
H
Ibanes
Sandy
S
Kalatzis
Vasiliki
V
Wang
Jennifer P
JP
Finberg
Robert W
RW
Cusack
Stephen
S
Kremer
Eric J
EJ
D000074183:ATPases Associated with Diverse Cellular Activities; D000256:Adenoviridae / Q000472:pathogenicity*; D000818:Animals; D001665:Binding Sites; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D004285:Dogs; D004912:Erythrocytes / Q000473:pathology* / Q000821:virology; D006384:Hemagglutination; D006801:Humans; D008666:Metalloendopeptidases; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D019158:N-Acetylneuraminic Acid