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Journal of Virology, October 2001, p. 8957-8967, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.8957-8967.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Antigenically Distinct Conformations of
CXCR4
Frédéric
Baribaud,1
Terri G.
Edwards,1
Matthew
Sharron,1
Anne
Brelot,2
Nikolaus
Heveker,2
Ken
Price,3
Frank
Mortari,3
Marc
Alizon,2
Monica
Tsang,3 and
Robert W.
Doms1,*
Department of Microbiology, University of
Pennsylvania, Philadelphia, Pennsylvania
191041; INSERM U332, Institut Cochin
de Génétique Moléculaire, 75014 Paris,
France2; and R&D Systems, Minneapolis,
Minnesota 554133
Received 22 March 2001/Accepted 23 June 2001
The major human immunodeficiency virus type 1 (HIV-1) coreceptors
are the chemokine receptors CCR5 and CXCR4. The patterns of expression
of the major coreceptors and their use by HIV-1 strains largely explain
viral tropism at the level of entry. However, while virus infection is
dependent upon the presence of CD4 and an appropriate coreceptor, it
can be influenced by a number of factors, including receptor
concentration, affinity between envelope gp120 and receptors, and
potentially receptor conformation. Indeed, seven-transmembrane domain
receptors, such as CCR5, can exhibit conformational heterogeneity,
although the significance for virus infection is uncertain. Using a
panel of monoclonal antibodies (MAbs) to CXCR4, we found that CXCR4 on
both primary and transformed T cells as well as on primary B cells
exhibited considerable conformational heterogeneity. The conformational
heterogeneity of CXCR4 explains the cell-type-dependent ability of
CXCR4 antibodies to block chemotaxis to stromal cell-derived
factor 1
and to inhibit HIV-1 infection. In addition, the MAb
most commonly used to study CXCR4 expression, 12G5, recognizes only a
subpopulation of CXCR4 molecules on all primary cell types analyzed. As
a result, CXCR4 concentrations on these important cell types have been
underestimated to date. Finally, while the factors responsible for
altering CXCR4 conformation are not known, we found that they do not
involve CXCR4 glycosylation, sulfation of the N-terminal domain of
CXCR4, or pertussis toxin-sensitive G-protein coupling. The fact that
this important HIV-1 coreceptor exists in multiple conformations could
have implications for viral entry and for the development of receptor antagonists.
*
Corresponding author. Mailing address: Department of
Microbiology, University of Pennsylvania, 225 Johnson Pavilion,
Philadelphia, PA 19104. Phone: (215) 898-0890. Fax: (215) 573-2883. E-mail: doms{at}mail.med.upenn.edu.
Journal of Virology, October 2001, p. 8957-8967, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.8957-8967.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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