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J. Biol. Chem., Vol. 277, Issue 13, 11456-11464, March 29, 2002
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From the Drug toxicities associated with HAART lend
urgency to the development of new anti-HIV therapies. Inhibition of
viral replication at the entry stage of the viral life cycle is an
attractive strategy because it prevents de novo infection.
Soluble CD4 (sCD4), the first drug in this class, failed to suppress
viral replication in vivo. At least three factors
contributed to this failure: sCD4 demonstrated poor neutralizing
activity against most primary isolates of HIV in vitro; it
demonstrated an intrinsic capacity to enhance viral replication at low
concentrations; and it exhibited a relatively short half-life in
vivo. Many anti-gp120 monoclonal antibodies, including
neutralizing monoclonal antibodies also enhance viral replication at
suboptimal concentrations. Advances in our understanding of the events
leading up to viral entry suggest strategies by which this activity can
be diminished. We hypothesized that by constructing a sCD4-based
molecule that is large, binds multiple gp120s simultaneously, and is
highly avid toward gp120, we could remove its capacity to enhance viral
entry. Here we describe the construction of a polymeric CD4-IgG1 fusion
protein. The hydrodynamic radius of this molecule is ~12
nM. It can bind at least 10 gp120 subunits with binding
kinetics that suggest a highly avid interaction toward
virion-associated envelope. This protein does not enhance viral
replication at suboptimal concentrations. These observations may aid in
the design of new therapeutics and vaccines.
Biochemical and Biological Characterization of a Dodecameric
CD4-Ig Fusion Protein
IMPLICATIONS FOR THERAPEUTIC AND VACCINE STRATEGIES*
§¶,§,,,,,,,
,,,, and
Laboratory of Immunoregulation, NIAID, and
the Molecular Interactions Resource Division of Bioengineering
and Physical Science, National Institutes of Health,
Bethesda, Maryland 20892
*
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.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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