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Journal of Virology, July 2001, p. 6682-6686, Vol. 75, No. 14
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.14.6682-6686.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Structural Flexibility and Functional Valence of CD4-IgG2
(PRO 542): Potential for Cross-Linking Human Immunodeficiency Virus
Type 1 Envelope Spikes
Ping
Zhu,1
William C.
Olson,2 and
Kenneth H.
Roux1,*
Department of Biological Science and Structural Biology
Program, Florida State University, Tallahassee, Florida
32306,1 and Progenics Pharmaceuticals,
Inc., Tarrytown, New York 105912
Received 16 February 2001/Accepted 18 April 2001
 |
ABSTRACT |
CD4-immunoglobulin G2 (CD4-IgG2) incorporates four copies of the
D1D2 domains of CD4 into an antibody-like molecule that potently neutralizes primary human immunodeficiency virus type 1. Here electron
microscopy was used to explore the structure and functional valence of
CD4-IgG2 in complex with gp120. CD4-
2, a divalent CD4-immunoglobulin
fusion protein, was evaluated in parallel. Whereas CD4-2-gp120
complexes adopted a simple Y-shaped structure, CD4-IgG2-gp120
complexes consisted of four gp120s arrayed about a central CD4-IgG2
molecule, a structure more reminiscent of complement C1q. Molecular
modeling corroborated the electron microscopy data and further
indicated that CD4-IgG2 but not CD4-2 has significant potential to
cross-link gp120-gp41 trimers on the virion surface, suggesting a
mechanism for the heightened antiviral activity of CD4-IgG2.
| |
TEXT |
CD4-immunoglobulin G2
(CD4-IgG2; PRO 542) is a recombinant antibody-like fusion protein
wherein the heavy- and light-chain variable domains of human IgG2 have
been replaced with the D1D2 domains of human CD4 (2).
CD4-2 is a homodimer comprising D1D2 genetically fused to the hinge
and Fc region of the 2 heavy chain (2). Unlike
monovalent and divalent CD4-based proteins, CD4-IgG2 broadly and
potently neutralizes primary human immunodeficiency virus type 1 (HIV-1) isolates (3, 7, 9, 10, 28, 29) and has
demonstrated encouraging antiviral activity in humans (14,
25). In this study, we used electron microscopy (EM) and
molecular modeling to explore the structures of CD4-IgG2 and CD4-2
alone and in complex with gp120. These data were used to estimate the
ability of these agents to cross-link gp120s either within or between
the trimeric envelope spikes on the virion surface.
Immunoelectron microscopy.
Negative-staining immunoelectron
microscopy was performed as described previously (22, 23).
Individually, neither CD4-IgG2 nor CD4-2 produced interpretable
images typical of IgG molecules. Both appeared to be considerably
reduced in mass compared to IgG and often lacked distinctive Fc and Fab
arms (data not shown), observations that are not unexpected given that
the CD4 D1D2 components are more filamentous (narrow) than the IgG Fab
arms they replace.
However, interpretable images emerged when both molecules were reacted
with recombinant, monomeric HIV-1JR-FL gp120
(27). CD4-2-gp120 complexes (Fig.
1A) typically appeared as trilobed structures comprising two rounded structures (putative gp120s) in
association with a smaller ovoid structure (putative Fc). The rounded
and ovoid structures were sometimes separated by a gap that was often
bridged by a thin filament (putative D1D2). The spatial relationships
between the structures were variable, suggesting considerable segmental
flexibility. To establish the identities of the individual elements of
the complexes, they were reacted with a monoclonal antibody (MAb) to
human IgG Fc (MAb 1302; Chemicon, Temecula, Calif.). This approach lead
to the formation of four-membered ring structures with fixed geometries
composed of two anti-Fc MAbs cross-linking two CD4-2 molecules (Fig.
1B). In these images, gp120 and Fc are identified unequivocally. Up to
two gp120 molecules laterally protrude from opposite sides of the
complexes and appear to be attached by filamentous arms. Complexes
formed in the absence of gp120 did not display the lateral globular
structures (data not shown).
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FIG. 1.
Electron micrographs and interpretive diagrams of
CD4-2 and CD4-IgG2 in complex with monomeric recombinant
HIV-1JR-FL gp120. Bar = 50 nm. (A) CD4-2 and gp120;
(B) CD4-2, gp120, and anti-Fc MAb; (C) CD4-IgG2 and gp120; (D)
CD4-IgG2, gp120, and anti-Fc MAb.
|
|
CD4-IgG2-gp120 complexes (Fig.
1C) typically consisted of four
irregular spheres (putative gp120s) arrayed about a smaller
central
structure (putative Fc). The putative gp120s were clearly
attached to
the central structure by thin strands. These images
resemble those
obtained for C1q (
26), whose central stalk often
binds
perpendicular to the membrane while the six arms with their
globular
heads protrude radially. When anti-Fc MAb is added, the
many attached
gp120s form a crowded image wherein some of the
gp120s may be folded
back over one another or over the Fc. Nevertheless,
at least three
gp120s per CD4-IgG2 are seen in most of the complexes
(Fig.
1D).
Compared with IgG, the Fab arms of CD4-IgG2 appear
less compact,
consistent with their ability to project radially
and independently of
one another. In this arrangement, each arm
would serve as a flexible
tether for gp120. The results demonstrate
that CD4-IgG2 can bind four
gp120 monomers simultaneously with
minimal steric interference between
D1D2
domains.
Molecular modeling of CD4-IgG2 and CD4-2 in complex with
monomeric gp120, trimeric gp120 and arrays of trimeric gp120.
Models were constructed using the SwissPDBviewer
(http://www.expasy.ch/spdbv/text/index.htm) and the O Protein
Crystallographic Package (http://imsb.au.dk/~mok/o/) and used
to lend support to the EM-based interpretations and investigate
the likely mode of binding to viral surfaces. The CD4-IgG2 model was
constructed using the constant regions of human IgG1
Fab 3D6
(Protein Data Bank [PDB] access code 1DFB [12]), the
Fc domain of human IgG1 antibody POT (PDB code 1FC1
[4]), and the D1D2 domains of CD4 (PDB code 1CDH
[24]). Amino acids and disulfide bonds in the hinge and
surrounding regions were converted from IgG1 to IgG2 and structurally
refined using O. D1D2 (K1 to F179) was grafted onto A114 of the
CH1 domain and T109 of the light chain (Kabat
numbering [15]). The CD4-2 model was constructed by linking D1D2 to E226 of the 2 hinge region.
Models of CD4-
2 and CD4-IgG2 in complex with monomeric gp120 were
constructed using the X-ray structure of the gp120 core
in complex with
D1D2 and Fab 17b (PDB code
1GC1 [
16]).
The model of CD4-
2 in complex with gp120 (Fig.
2A) is consistent with
the EM images in that the three lobes correspond to
the Ig Fc (blue)
and two CD4 D1D2 domain pairs (yellow) in complex
with two gp120s
(orange). For CD4-IgG2-gp120 complexes, four gp120s
could easily be
arrayed about a central Fc standing "on end" (e.g.,
compare Fig.
2B
and
1C). In contrast to the more compact structure
of intact IgG Fab,
the CD4 arms of CD4-IgG2 protrude tangentially
from the
C
L (green) and C
H1 domains
(blue), providing considerable
flexibility with minimal steric
inhibition. Thus, CD4-IgG2 appears
to be functionally tetravalent. The
CD4-IgG2-gp120 model is shown
in a side view in Fig.
2C for
comparison.
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FIG. 2.
Models of monomeric (A to C) and trimeric (D) gp120
cores in complex with CD4-2 and CD4-IgG2. (A) CD4-2 with
monomeric gp120; (B and C) top and side views, respectively, of
CD4-IgG2 with monomeric gp120; (D) CD4-IgG2 with trimeric gp120. For
clarity, only two of the four D1D2 domains of CD4-IgG2 are shown in
panel D. Color codes: blue, Ig heavy chain; red, IgG2 hinge region
disulfide bonds; green, light-chain C domain; yellow, D1D2 domains
of CD4-IgG2; orange, gp120 core. The pink structure in panel D
represents the D1D2 domains docked in the nearest CD4 binding site not
occupied by CD4-IgG2 and is included for orientation purposes. Note
that the left-hand CD4 arm (yellow) of CD4-IgG2 is unable to extend and
maneuver into the requisite docking position (pink CD4) of the
left-hand gp120 subunit.
|
|
The potential for polyvalent interaction (i.e., cross-linking) of a
single anti-gp120 construct with a single gp120 trimer,
as would appear
on a viral or infected-cell surface, was tested.
Trimeric gp120
(orange) was modeled as described previously (
17).
Upon
docking with CD4-IgG2 (Fig.
2D) and CD4-
2 (data not shown),
it was
apparent that no amount of flexibility in the hinge,
C
H1,
or C
L regions would
allow cross-linking of intratrimer gp120s.
Intratrimer cross-linking
would require rotation of the D1 and
D2 domains relative to one another
such that significant steric
clashes occur (data not shown). Thus,
neither molecule appears
to be capable of cross-linking intratrimer
gp120s, as originally
suggested (
17).
Various biochemical, crystallographic, EM, and modeling data suggest
that the p17 matrix protein forms trimers that are organized
into a
paracrystalline icosahedral matrix below the membrane of
mature virions
(
6,
13,
21), forming a mesh of interconnected
rings into
which the cytoplasmic tail of gp41 may insert (
6).
This
pattern positions the envelope trimers at the vertices of
equilateral
triangles having a center-to-center distance of 210
Å. The model is
consistent with EM data indicating an initial
70 to 80 envelope
spikes per virion (pre-gp120 shedding) and similar
center-to-center
distances (
11,
20,
21).
Based on this information, a symmetric assembly of gp120 trimers was
constructed to test for the possibility of intertrimer
cross-linking.
Trimers were first rotated so as to orient the
CD4 binding site
(occupied by phantom pink CD4 D1D2 molecules
[Fig.
3]) toward neighboring trimers. When
docked into CD4 binding
sites of one such trimer (Fig.
3A, arrow),
CD4-IgG2 spanned to
two adjacent trimers, but none of the free D1D2
domains (yellow)
was in a position compatible with docking. We next
rotated each
of the trimers 20° clockwise so as to place the C
termini of bound
D1D2 segments in closest proximity. When an initial
D1D2 domain
of CD4-IgG2 was fully docked (Fig.
3B, white arrow), two
additional
CD4s either overshot (green arrow) or undershot (yellow
arrow)
adjacent trimers by 12 and 23 Å, respectively. In a third
model,
we rotated each of the gp120 trimers in unison to search for
other
configurations that could accommodate cross-linking. Figure
3C
shows one orientation (45° clockwise with respect to Fig.
3A)
favorable for two fully docked CD4 arms. A final model allowed
free
rotation of the gp120 trimers. The most favorable of the
configurations
were similar to that in Fig.
3C and allowed two
but not three arms of
CD4-IgG2 to fully dock (data not shown).
It should be noted that our
model assumes that the D1D2 domains
remain rigid. Any additional
segmental flexibility would further
increase the potential for
cross-linking. Because of its smaller
reach (165 versus 220 Å for
CD4-IgG2), CD4-
2 fell 40 to 50 Å
short of cross-linking even
optimally oriented trimers (data not
shown). The implications of these
observations are currently being
tested through experimental studies of
the detailed stoichiometry
of virus neutralization by these molecules.
In additional studies,
we are examining whether cross-linking is
possible with anti-gp120
antibodies, which are intermediate in size
between CD4-
2 and
CD4-IgG2 and can target additional neutralization
epitopes outside
the CD4 binding site.
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FIG. 3.
Models of CD4-IgG2 in complex with arrays of gp120
trimers. (A) Docking of CD4-IgG2 with trimers oriented such that the
CD4 binding sites project toward neighboring trimers. (B and C) gp120
trimers are rotated 20° and 45° clockwise with respect to those in
panel A. Arrows indicate CD4 arms that closely approach (yellow and
green) or fully engage (white) a CD4 binding site of gp120. Structures
are color coded as described for Fig. 2.
|
|
There are numerous uncertainties as to the orientation of gp120 on the
viral surface, limiting our ability to draw firm conclusions
regarding
cross-linking. First, only the CD4-bound conformation
of gp120 is
known, whereas the target gp120 molecule is in the
native
configuration. Also, little is known regarding the geometry
and
flexibility of the gp120-gp41 interaction. Similarly, the
rotational
and diffusional freedom of the envelope spikes is poorly
understood
(
1,
5,
8,
19,
30). Lastly, cross-linking
may be variably
affected by host cell proteins incorporated into
the viral
membrane.
In addition, mechanisms other than trimer cross-linking may contribute
to the heightened antiviral activity of CD4-IgG2. First,
the higher
valence of CD4-IgG2 serves to increase the likelihood
that a second
gp120 will be engaged before CD4-IgG2 diffuses away
from the virion
surface following gp120 stripping or dissociation
of the
CD4-IgG2-gp120 complex (
18). Second, the steric effect
of
CD4-IgG2 binding may significantly hinder gp120 interactions
with cell
surface CD4 or fusion coreceptors, either directly or,
because of its
size, indirectly by preventing close apposition
of virus and target
cell. Last and more conceptually, CD4-IgG2
may cross-link multiple
virions and thereby accelerate their clearance.
Additional studies are
needed to distinguish between these
alternatives.
In summary, we have used negative-stain immunoelectron microscopy to
demonstrate that CD4-
2 and CD4-IgG2 are functionally
divalent and
tetravalent, respectively, in binding monomeric gp120,
i.e., there is
no steric inhibition between CD4 arms. Molecular
models are consistent
with the electron microscopic images and
have been used to explore the
interactions of these molecules
with trimeric gp120. The models reveal
that CD4-IgG2 but not CD4-
2
has considerable potential to cross-link
envelope trimers on the
virion
surface.
| |
ACKNOWLEDGMENTS |
We thank Wayne Hendrickson and John Moore for critical reading of
the manuscript.
This work was supported in part by NIH grants R21 AI44291 and R01 AI43084.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Biological Science, Biology Unit I, Florida State University,
Tallahassee, FL 32306-4370. Phone: (850) 644-5037. Fax: (850) 644-0481. E-mail: roux{at}bio.fsu.edu.
| |
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Journal of Virology, July 2001, p. 6682-6686, Vol. 75, No. 14
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.14.6682-6686.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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