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J. Biol. Chem., Vol. 277, Issue 26, 23709-23713, June 28, 2002
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From the Departments of Adeno-associated virus (AAV) is a promising
vector for gene transfer in cystic fibrosis. AAV4 and AAV5 both bind to
the apical surface of differentiated human airway epithelia, but only
AAV5 infects. Both AAV4 and AAV5 require 2,3-linked sialic acid for binding. However, AAV5 interacts with sialic acid on
N-linked carbohydrates, whereas AAV4 interacts with sialic
acid on O-linked carbohydrates. Because mucin is decorated
with O-linked carbohydrates, we hypothesized that mucin
binds AAV4 and inhibits gene transfer. To evaluate the effect of
secreted mucin, we studied mucin binding and gene transfer to COS cells
and the basolateral membrane of well differentiated human airway
epithelia. AAV4 bound mucin more efficiently than AAV5, and
mucin inhibited gene transfer with AAV4. Moreover,
O-glycosidase-pretreated mucin did not block gene transfer
with AAV4. Similar to secreted mucin, the transmembrane mucin MUC1
inhibited gene transfer with AAV4 but not AAV5. MUC1 inhibited AAV4 by
blocking internalization of the virus. Thus, O-linked
carbohydrates of mucin are potent inhibitors of AAV4. Furthermore,
whereas mucin plays an important role in innate host defense, its
activity is specific; some vectors or pathogens are more resistant to
its effects.
Secreted and Transmembrane Mucins Inhibit Gene Transfer with AAV4
More Efficiently than AAV5*
§,
**, and
Internal Medicine and
§ Physiology and Biophysics, University of Iowa College of
Medicine, Iowa City, Iowa 52242, the ¶ Department of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and the
Gene Therapeutics Branch, NIDCR, National Institutes of Health,
Bethesda, Maryland 20892
*
This work was supported in part by the Center for Gene
Therapy, NIDDK, National Institutes of Health Grant T30DK54759, the Cystic Fibrosis Foundation, and the Roy J. Carver Charitable
Trust.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed: University of Iowa
College of Medicine, 500 EMRB, Iowa City, IA 52242. Tel.: 319-353-5511; Fax: 319-335-7623; E-mail: joseph-zabner@uiowa.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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