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*
Département d’Immunologie and
Unité des Venins, Institut Pasteur, Paris, France;
Centre for Rheumatology, Bloomsbury Rheumatology Unit, Department of Medicine, University College London, London, United Kingdom; and
§
Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to this bacterial SAg, there is evidence that viruses can produce B cell SAgs. In contrast to its interaction with immunization-induced Abs through conventional Ag binding which requires the tertiary structure of the heavy and light chain variable regions, the envelope glycoprotein gp120 of HIV-1 reacts also with normal human nonimmune Igs and B cells expressing members of the VH3 gene family, independently of the light chain isotype, and of DH and JH usage. This unconventional interaction results in activation and differentiation of nonimmune VH3+B cells (14). Since the VH3 gene family dominates (>50%) the human Ab expressed repertoire (15, 16, 17), the SAg properties of gp120 may induce alterations in the B cell repertoire with potential pathologic consequences in HIV-infected individuals (3). For instance, a progressive depletion of VH3+ B cells was seen during late stages of HIV infection (18, 19). However, the molecular mechanisms underlying this B cell-specific depletion remain the focus of investigation. Recently, the SAg residues engaged in binding to VH3+ Igs have been identified (20, 21). Yet, the precise topology of interaction between gp120-encoded residues and Ig residues remains unknown. Also unresolved is the repertoire of VH3+ Igs that can interact with gp120. Here, we have used human mAbs of known VHDHJH sequences to determine the spectrum of VH3+ Igs capable of gp120 binding and to delineate the structural basis of this interaction by means of molecular modeling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recombinant HIV-1MN gp120 was obtained through the
AIDS Research and Reference Reagent Program (Division of AIDS, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD) from MicrogeneSys (West Haven, CT). Human
monoclonal IgG and IgM expressing different VH gene family
genes were obtained from different sources. Their molecular
characteristics are summarized in Table I
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Direct binding was assessed by ELISA. Polystyrene microtiter plates (Maxisorp F96, Nunc Laboratories, Glostrup, Denmark) were incubated overnight at 4°C with 100 µl of gp120MN (50 ng/well) diluted in borate-buffered saline (pH 8.4). Plates were washed with PBS (pH 7.2) containing 0.1% Tween 20 (Prolabo, Fontenay-sous-Bois, France) (PBS-Tween), and nonspecific sites of the wells were blocked with PBS containing 1% (w/v) of BSA (PBS-BSA) for 2 h at 37°C. A 100-µl volume of the test Ab diluted in PBS-BSA was added to each well, and, after 90 min of incubation at 37°C, the plates were washed again with PBS-Tween. Bound Abs were revealed with an alkaline phosphatase-labeled anti-Ig conjugate. After a further incubation for 1 h at 37°C, the plates were washed with PBS-Tween, and a volume of 100 µl per well of the alkaline phosphatase substrate p-nitrophenyl phosphate (Sigma, St. Louis, MO) (1 mg/ml) diluted in 0.05 M carbonate buffer, pH 9.5, containing 2 mM MgCl2 was added. Optical density was recorded at 405 nm with a multiscan automatic plate reader (MR 5000, Dynatech Labs, Chantilly, VA).
Binding of Igs to SpA
SpA expresses binding sites for both VH3+ Igs and the constant region domain of IgG. Iodine monochloride modification of SpA selectively inactivates IgG-binding activity of protein A, without affecting its Fab-mediated binding (40, 41). We treated SpA (Sigma) with iodine chloride to inactivate its Fc-binding site (Mod-SpA). The Mod-SpA was then biotinylated. Both forms of SpA were used in an ELISA assay as described above.
Amino acid sequence analysis
Ig amino acid (aa) sequences were obtained from the current GenBank/EMBL data base. They were aligned using the Clustal V algorithm (D. Higgins, European Molecular Biology Laboratory) using default settings. The aa were classified in four groups: nonpolar (Ala, Val, Leu, Ile, Pro, Phe, Met, and Gly); polar (Trp, Ser, Thr, Cys, Tyr, Asn, and Gln); acidic (Asp and Glu); and basic (Lys, Arg, and His). First, the 3-23 germline gene-encoded, gp120 positive, 18/2 Ab was used as a template for sequence comparison of gp120-positive Igs. The 3-23 gene is supposed to be closest to the consensus sequence of VH3 germline configuration genes. Then, the sequences of gp120-negative Igs were compared with those of gp120-positive Igs. Substitutions leading to expression of an aa from a different aa group were considered nonconservative. For each aa position, the percentage of replacement changes was calculated by dividing the number of nonconservative substitutions by the number of Abs tested. When an aa was unknown, or when there was a deletion, the Ab was not counted.
Molecular modeling and simulations
The structure of the 18/2 Ab was modeled using the coordinates from the crystal structure of a highly sequence homologous human Ig. Calculations were conducted and visualized on a SGI graphics work station using the software InsightII/95.0 (MSI, Cambridge, U.K.). A homology-based 3D model of 18/2 was obtained using the HOMOLOGY facility of InsightII. The resulting preliminary model was refined by performing a side chain rotamer search to alleviate unfavorable interatomic contacts whenever they were present. The solvent accessible molecular surface of 18/2 Ab was calculated using a probe radius of 1.4 Å. Atomic radii used are: C 1.55 Å, H 1.10 Å, O 1.35 Å, S 1.81 Å, and N 1.40 Å.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gp120 and SpA binding is restricted to human VH3+ Igs
To define the extent of the repertoire used by human Igs binding
to HIV-1 gp120, we tested the Ig panel for binding to
gp120MN by ELISA. None of VH1+,
VH4+, and VH5+ Igs
bound to gp120, confirming previous findings that the binding of gp120
to human Igs is restricted to Abs using VH3 gene segments
(14). However, among the 26 VH3+ Igs, only 27%
(four IgM and three IgG) bound gp120 (Table I
). To see whether this low
proportion of gp120 binders was due to a selection bias in the panel
used, we tested reactivity of all the Igs with SpA, the prototypic SAg
for human VH3+ B cells (5, 6, 7, 8). Comparative
binding to Mod-SpA showed that 77% (20 of 26) of
VH3+ Igs bound to SpA, indicating that gp120
interacts with only a subset of VH3+ Igs that
can convey SpA binding. However, among the gp120 binders, RSP-4, a
VH3+ Ig, did not bind Mod-SpA, suggesting that
there may be unusual examples in which a somatic mutation interferes
primarily with the SpA binding with little or no effects on the gp120
binding.
The observation that all SpA+ VH3+
Igs are not positive for gp120 and that all gp120 binders do not
interact with SpA suggests that these two SAgs might use different
sites to contact VH3+ Igs. This possibility was
tested in an experiment designed to probe whether SpA and gp120 target
the same sites on VH3+ Igs. A purified
VH3+ IgG (SAU) with binding specificity to SpA
and gp120 (21) was first incubated with gp120-coated wells; then,
biotinylated Mod-SpA was added at different concentrations. Formation
of gp120-IgG-SpA-biotin complexes was revealed by an alkaline
phosphatase-labeled Extravidin conjugate (Sigma). In the absence
of biotinylated Mod-SpA, no IgG binding to gp120 was seen (Fig. 1). In the presence of biotinylated
Mod-SpA, there was a dose-dependent binding activity of IgG to gp120,
suggesting that gp120 and SpA may use different Ig motifs for SAg
binding. However, we cannot rule out the possibility that the same, or
overlapping, VH sites are involved or that gp120 has more
rigorous conformational requirements for binding. Also, subtle
conformational variations from a prototypic Ig structure might be
permissive for SpA binding, while they are unfavorable for gp120
binding. Finally, the bivalency of the IgG molecule could allow one
VH region to bind gp120 on the plate, leaving the other
VH available for Mod-SpA binding.
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To characterize the variable gene products that impart gp120
binding, we analyzed in detail the sequences of the
VH3+ Igs. It was clear that gp120-positive Igs
used a variety of DH and JH gene segments,
together with diverse VL and JL gene
elements (Table I). With regard to VH gene usage, only
three VH3+ germline gene donors were
encountered, namely 3-23, 3-30, and 3-73 genes, and in all cases the
expressed genes were highly homologous (96–100%) to germline
configuration. By contrast, the VH3 genes utilized by
gp120-negative Igs were, generally, more divergent from the
corresponding germline homologues, encompassing between 2 and 15 aa
substitutions (data not shown). It seems therefore that the repertoire
of gp120 SAg Ig binders is restricted to a limited number of
VH3 genes and that gp120 binding is sensitive to somatic
mutations. These characteristics contrast with the diversity of the
VH3 genes that impart SpA binding. The positive Igs were
derived from eight VH3 germline genes (3-7, 3-11, 3-21,
3-23, 3-30, 3-30.3, 3-33, and 3-73), and the 3-23 and 3-30 genes were
the most frequently encountered. This finding is in agreement with
previous results which were interpreted as evidence of hierarchy in the
SpA binding affinity conveyed by different VH3 genes, in
which V3-23 was predominant (6).
Putative regions of VH3+ Igs involved in gp120 superantigen binding
The aa sequences of the VH3+ Igs were
analyzed to determine whether there was a common motif that could
account for gpl20 binding activity. To enhance the significance of the
sequence comparisons, three Igs, TaaO, NANUC1, and NANUC2, with binding
specificity for gp120 (42) were added to the Ig panel. NANUC1 and
NANUC2 are human Igs encoded by the 3-30 VH gene (43). TaaO
is a mouse Ig belonging to Ig clan 3, which is a group of structurally
related Ig VH gene families from different species, the
greatest homologies being in the FR1 and FR3 (44). Since Igs expressing
the 3-23 VH gene are the most frequently expressed in the
human repertoire (see Discussion), we used the 3-23 germline
gene-encoded 18/2 Ab as a template to align the aa sequences of the Ig
panel (Fig. 2). First, we calculated the
percentage of nonconservative aa substitutions in the sequences of the
nine gp120-positive proteins, the six Igs represented in Table I and
the three Igs described above. This sequence comparison revealed aa
conservations, mainly in the FR regions. With the exception of FR2
which is inaccessible to the solvent (45), some of these conserved
residues likely play a role in gp120 recognition by
VH3+ proteins. Reciprocally, the substituted
positions probably do not interfere with gp120 binding ability (Fig. 3).
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), it became
apparent that the regions critical for gp120-Ig interaction might lie
in the FR1 (aa positions 10, 13, 19, and 23), in the H1 (aa positions
28 and 32), in the H2 (aa position 54), and in the FR3 (aa positions,
59, 64, 65, 75, 79, 81, 82a, 83, and 85). Modeling
To define the surface residues that may participate in gp120 SAg
binding, we constructed a model for the structure of 18/2 Ab based on
known structures of Ig domains. Within the limitations of such models,
certain inferences can be drawn from the basic similarities of highly
homologous Igs to predict residue exposures and spatial orientations.
The heavy chain of a crystallized human IgM Fv fragment (Protein
Database code 1igm) was selected for modeling (46). The
potential putative contact sites are shown in Fig. 4. The side chains of all the residues
identified and the backbone of the three glycines are solvent exposed.
Moreover, most of the residues are located on the face of the Ab
opposite to the interface between the heavy and light chains. On that
side, they form essentially two major clusters extending from residue
Lys75 to residue Lys64. The larger is composed
of Lys75, Ala23, Tyr79,
Arg19, Gln81, and Asn82a and has a
linear ridge-like shape. The second cluster encompasses residues
Tyr59, Gly65, and Lys64, which are
in close proximity and exhibit a triangular configuration. Residue
Gln54 on one hand, and residues Gln13 and
Arg83 on the other, are located on either side of this
patch. The remaining residues fall rather away from this area, i.e., in
the conventional Ag binding site (Thr28 and
Tyr32 of H1), or in the lower right hand of the figure
(Gly10 of FR1). Overall, the convex shaped area contains
polar residues such as Gln81 and Asn82a and is
bordered by four positively charged residues arranged perpendicularly
in two pairs (Lys75-Arg19, and
Lys64-Arg83). The interatomic distances between
the Cß atoms of Lys75 and Lys64
and of Arg19 and Arg83 approximate 26 and 17
Å, respectively. Thus, the gp120-binding site of Igs consists of
nonsequential residues, which can be modeled to fold in space into a
solvent-exposed accessible compact region.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A restricted subset of Ig VH genes are responsible for gp120 SAg binding
This study showed that gp120 SAg binding is restricted to
VH3+ Igs and that it requires contribution from
a limited number of VH3+ gene products. Among
the 10 VH3+ genes expressed by the Ab panel
tested, only 27% (3-23, 3-30, and 3-73 VH genes) were used
by gp120 binders (40% of VH3+ IgM and 18% of
VH3+ IgG). In agreement with this low
proportion of reactive Igs, previous studies showed that only 
25%
of VH3+ human Igs and B cells bind gp120 (14, 42). Since in these studies, the 3-15 VH3 gene product was
also identified by an antiidiotypic reagent to encode gp120 binding, it
appears that, in toto, only four VH genes, 3-23, 3-30,
3-73, and 3-15, have been found to be responsible for gp120 SAg
binding. This restriction contrasts with the high frequency of SpA
binding among VH3+ Igs found here (80% of
VH3+ IgM and 75% of
VH3+ IgG) and elsewhere (85% of
VH3+ IgM, and 65% of
VH3+ IgG) (6). We also noted that gp120 may be
recognized by VH3+ Ig that do not interact with
SpA (4). It is of further interest that some SpA-negative,
VH3+ IgG were found to bind pFv, another
well-characterized SAg for B cells, and that pFv is also recognized by
VH6+ IgM that do not interact with SpA (47).
Thus, the three prototypic SAgs for human VH3+
B cells, SpA, gp120, and pFv, seem to target overlapping subsets of the
Ab repertoire (4).
A possible explanation of the relatively low frequency of gp120 Ig
binders is that the SAg-Ig interaction is highly sensitive to mutation.
We found that the VH genes used by gp120-positive Igs
exhibit >96% aa similarity to V3-30 germline gene (Table II) and that V3-30 gene-encoded Igs with
<96% similarity lose this capacity, thus suggesting that
hypermutation may have an adverse effect on gp120 binding. This inverse
correlation between the degree of somatic mutation and gp120 binding is
similar to the previously reported binding pattern described for SpA
(22). However, gp120 binding may be even more sensitive, as most V3-30
and V3-23 gene products tested showed binding activity for SpA, whether
or not gp120 binding activity was retained (Table II). It is also
possible that certain combinations of D, JH,
VL, and JL gene elements create an
unfavorable conformation of the variable domain and abrogate gp120
binding. In parallel studies, it was found that protein Fv interacts
with a greater set of VH3+ IgG Abs than does
SpA, suggesting that hypermutation more commonly has an adverse effect
on SpA binding than upon protein Fv binding (47). These observations
imply that the positions and/or the nature of the mutations involved in
the contact sites on Igs of these B cell SAgs are different.
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The finding that only a limited number of VH3+
genes (3-23, 3-30, 3-73, and 3-15) can impart gp120 binding deserves
consideration with regard to the functional consequences of SAg
interaction on the B cell repertoire. On the surface, it might seem
that such a limited number of VH genes would result in
minimal repertoire triggering. However, three lines of evidence suggest
that Igs encoded by this restricted set of VH genes have
the potential to impact significantly the human B cell repertoire.
First, studies of human VH gene polymorphisms showed that
the 3-23 VH gene is present in all individuals tested to
date and that some subjects carry up to six copies (48). Secondly, its
is recognized that the 3-23 VH gene comprises 25% of
VH3 rearrangements expressed in B cell clones (49, 50, 51, 52).
Finally, a recent study of human VH gene utilization
throughout ontogeny revealed that 3-23, 3-30, and 3-15 VH
genes are expressed at the pre-B, the immature B, and the mature B cell
stages of normal adults and that 3-23 and 3-30 VH genes are
overexpressed at all stages of B cell development (53). Given this
overexpression, it may be concluded that gp120 targets a sizable
fraction of the human germline-encoded B cell repertoire. As a result,
25% of human B cells bear VH3+ Igs with a
binding capacity to gp120 (42).
Sites on the Ig VH chain that interact with human B cell superantigens
In addition to showing that SAgs for human B cells target distinct subsets of the Ab repertoire, our results indicate that the VH domain of a single Ig molecule can confer distinct reactivities with the viral SAg gp120 and the bacterial SAg SpA. Reciprocally, we found that some VH3+ Abs bind both gp120 and SpA. These observations imply that, apparently, these two SAgs are recognized by VH3+ Igs, through distinct sites or via overlapping contact residues. This property is reminiscent of parallel characteristics of T cell SAgs, where TCR binding was shown to differ for a bacterial SAg, staphylococcal enterotoxin E, and the retroviral SAg MTV-9 (54). In addition, a viral and a bacterial SAg were found to interact with distinct sites of the Vß domain of a single TCR (55). When two naturally occurring alleles of a TCR Vß gene were tested for staphylococcal enterotoxin E binding, their functional reactivities also differed (54). It seems therefore that, as is the case for T cell SAgs, there are distinct recognition sites for viral and bacterial SAgs for B cells. Nevertheless, it has been shown that Ig binding to protein Fv, a B cell SAg of endogenous origin, can be abrogated by SpA, or a single domain of SpA (22, 47).
Amino acid residues that mediate binding to VH3+ Igs
Comparison of the VH3+ sequences from gp120 Ig binders and nonbinders provides a basis to delineate the interaction site of gp120 with the Ig molecule. Since FR2 is not accessible to the solvent and, hence, is unlikely to be involved in gp120 binding (45), possible determinants that could be critical for gp120 binding were found in the FR1 (positions 10–23), the H1 (positions 28 and 32), the H2 (position 54), and the FR3 (positions 59–85), as there were nonconservative changes in these regions. Remarkably, 13 of the 16 aa positions identified map outside the conventional Ag-binding site, in the FR1 (residues 10, 13, 19, and 23), and the FR3 regions (residues 59, 64, 65, 75, 79, 81, 82a, 83, and 85). In addition, three positions localized in the H1 and H2 loops were identified that might influence gp120 binding.
Localization of the residues in Ig variable regions that contact SpA has been also the focus of interest. Sequence analyses of SpA-positive human Igs led to the suggestion that residues in FR1 (position 28), the carboxyl-terminal end of CDR2 (positions 57 and 59), and FR3 (positions 75, 76, 80, 82a, and 84) are critical for SpA binding (6, 11, 12). Recent experiments where regions of an SpA-positive human-derived Ab were exchanged with those from an SpA-nonreactive mouse Ab provided further evidence that the three regions, FR1, CDR2, and FR3, are required to interact simultaneously with SpA for binding to occur (13). Here, we have identified 16 aa positions localized in the FR1, H1, H2, and FR3 which correlate with gp120 binding. Among these, only residues 28, 75, and 82a overlap with the SpA binding site which encompasses at least eight residues.
Well-established similarities between the structures of the Ig variable domains and those of the TCR invite comparisons of their mode of interaction with SAgs. It may therefore be valid to extend this analogy to infer structural attributes of a B cell SAg from the recent three-dimensional structure characterization of T cell SAgs. Crystal structures of bacterial T cell SAgs, S. aureus enterotoxins C2 and C3, show that binding occurs via the CDR1, CDR2, FR3, and involves 12 contact residues of the TCR Vß chain and that residues implicated in TCR binding sit in a depression at the center of the surface while secondary structural elements protrude on either side (56). In other studies of T cell SAgs, the interaction with the TCR was also shown to involve the ß hairpin loop of the Vß FR3 region, which is structurally homologous to the FR3 region of the Ig molecule (55). Our data are consistent with a model in which the putative binding site for gp120 comprises 16 residues located in the solvent-exposed regions and strands of VH3+ Igs, primarily outside the conventional binding site. In this model, the points of contact between the two molecules represent a virtually continuous area, flanked by four basic side chains, and surrounded by aa residues 54 and 13 on either side. If charge and shape complementarity are to be observed, the contact surface presented by gp120 should be overall concave and acidic. Furthermore, the similarity in structures with the TCR would allow the VH FR3 region (corresponding to the hypervariable loop 4 in Vß) to make direct contacts with gp120 residues critical for binding (20, 21).
Recently, the x-ray crystallographic structure of gp120 has been elucidated at 2.5 Å resolution. It shows that a broadly neutralizing human mAb directed to the CD4-induced gp120 epitope uses essentially its heavy chain for binding. Additionally, the interaction between this Ab and gp120 involves a hydrophobic central region flanked by charged regions (57, 58). Our findings revealed that the potential putative contact sites of Ig SAg binding form essentially two major clusters and contain nonsequential polar residues bordered by positively charged residues. It will be important to determine the atomic structure of a complex of gp120 complexed to a human VH3+ Ig exhibiting the B cell SAg activity.
Note added in proof.
In a recent report (61), murine repertoire analyses provided the first evidence that in vivo experimental challenge with a form of SpA, the prototypic B cell superantigen, can induce specific large scale B cell clonal specific tolerance by deletional and nondeletional mechanisms. These findings represent independent support of a role for envelope protein, gp120, in the induction of superantigen-induced B cell clonal defects during clinical HIV infection.
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Acknowledgments |
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Footnotes |
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2 Current address: INSERM U25, Hôpital Necker Enfants Malades, 161 Rue de Sèvres, 75015 Paris, France.
3 Current address: Yerkes Regional Primate Research Center, 954 N. Gatewood Road, Atlanta, GA 30322.
4 Address correspondence and reprint requests to Dr. M. Zouali, Département d’Immunologie, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France. E-mail address:
5 Abbreviations used in this paper: aa, amino acid; H1, first hypervariable loop; H2, second hypervariable loop; H3, Third hypervariable loop; Mod-SpA, tyrosine-modified SpA; SAg, superantigen; SpA, Staphylococcus aureus protein A; CDR, complementarity-determining region; FR, framework region.
Received for publication May 5, 1998. Accepted for publication August 19, 1998.
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gene rearrangements. EMBO J. 13:2951.[Medline]
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, Unknown aa position. GenBank/EMBL
accession numbers are: 18/2, 
