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J. Biol. Chem., Vol. 275, Issue 31, 23774-23782, August 4, 2000
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From the Department of Microbiology and Immunology, Uniformed
Services University of the Health Sciences,
Bethesda, Maryland 20814-4799
CXCR4 and CCR5 are the principal coreceptors for
human immunodeficiency virus type-1 (HIV-1) infection. Previously,
mutagenesis of CXCR4 identified single amino acid changes that either
impaired CXCR4's coreceptor activity for CXCR4-dependent
(X4) isolate envelope glycoproteins (Env) or expanded its activity,
allowing it to serve as a functional coreceptor for
CCR5-dependent (R5) isolates. The most potent of these
point mutations was an alanine substitution for the aspartic acid
residue at position 187 in extracellular loop 2 (ecl-2), and here we
show that this mutation also permits a variety of primary R5 isolate
Envs, including those of other subtypes (clades), to employ it as a
coreceptor. We also examined the corresponding region of CCR5 and
demonstrate that the substitution of the serine residue in the
homologous ecl-2 position with aspartic acid impairs CCR5 coreceptor
activity for isolates across several clades. These results highlight a
homologous and critical element in ecl-2, of both the CXCR4 and CCR5
molecules, for their respective coreceptor activities. Charge
elimination expands CXCR4 coreceptor activity, while a similar charge
introduction can destroy the coreceptor function of CCR5. These
findings provide further evidence that there are conserved elements in
both CXCR4 and CCR5 involved in coreceptor function.
Substitutions in a Homologous Region of Extracellular Loop 2 of
CXCR4 and CCR5 Alter Coreceptor Activities for HIV-1 Membrane Fusion
and Virus Entry*
*
This study was supported by National Institutes of Health
Grant R01AI43885 and Uniformed Services University of the Health Sciences Grant RO73FG (to C. C. B.).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 should be addressed: Dept. of Microbiology
and Immunology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd.,
Bethesda, MD 20814-4799. Tel.: 301-295-3401; Fax: 301-295-1545; E-mail:
cbroder@mxb.usuhs.mil.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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