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Journal of Virology, June 1999, p. 4582-4589, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Enhanced Inhibition of Human Immunodeficiency Virus
Type 1 by Met-Stromal-Derived Factor 1
Correlates with
Down-Modulation of CXCR4
Otto O.
Yang,1
Stephen L.
Swanberg,2
Zhijian
Lu,2
Michelle
Dziejman,1
John
McCoy,2
Andrew D.
Luster,1
Bruce D.
Walker,1 and
Steven H.
Herrmann2,*
AIDS Research Center and Infectious Disease
Unit, Massachusetts General Hospital and Harvard Medical School,
Charlestown, Massachusetts 02129,1 and
Infectious Disease and Molecular Biology-Gene Expression,
Genetics Institute Inc., Cambridge, Massachusetts
021402
Received 2 November 1998/Accepted 22 February 1999
CXCR4 is a chemokine receptor used by some strains of HIV-1 as an
entry coreceptor in association with cell surface CD4 on human cells.
In human immunodeficiency virus type 1 (HIV-1)-infected individuals,
the appearance of viral isolates with a tropism for CXCR4 (T tropic)
has been correlated with late disease progression. The presumed natural
ligands for CXCR4 are SDF-1
and SDF-1
, which are proposed to play
a role in blocking T-tropic HIV-1 cell entry. Here, we demonstrate that
addition of an N-terminal methionine residue to SDF-1
(Met-SDF-1
)
results in a dramatically enhanced functional activity compared to that
of native SDF-1
. Equivalent concentrations of Met-SDF-1
are
markedly more inhibitory for T-tropic HIV-1 replication than SDF-1
.
A comparison of the biological activities of these two forms of
SDF-1
reveals that Met-SDF-1
induces a more pronounced
intracellular calcium flux yet binds with slightly lower affinity to
CXCR4 than SDF-1
. Down-modulation of CXCR4 is similar after exposure
of cells to either chemokine form for 2 h. However, after a 48-h
incubation, the surface expression of CXCR4 is much lower for cells
treated with Met-SDF-1
. The enhanced blocking of T-tropic HIV-1 by
Met-SDF-1
appears to be related to prolonged CXCR4 down-modulation.
*
Corresponding author. Mailing address: Infectious
Disease Research, Wyeth-Cambridge, Genetics Institute, 87 Cambridge
Park Dr., Cambridge, MA 02140. Phone: (617) 498-8245. Fax: (617)
498-8878. E-mail: sherrmann{at}genetics.com.
Journal of Virology, June 1999, p. 4582-4589, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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