Neutralizing activity of anti-peptide antibodies against the principal neutralization domain of human immunodeficiency virus type 1

Langedijk, J.P.M.; Back, Nicole K. T.; Durda, Paul J.; Goudsmit, Jaap; Meloen, Rob H.

doi:10.1099/0022-1317-72-10-2519

Cited by 33 publications

(28 citation statements)

References 30 publications

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“…By SPR, the affinities of both antibodies for RK and CRK were measured to be the same, within experimental error (data not shown). The 5023A and 5025A affinities for RK peptide (data not shown) were similar to those published earlier and determined by modified enzymelinked immunosorbent assay (47). It was determined from microcalorimetry experiments that 5023A and 5025A do not bind appreciably to BPTI (data not shown).…”

Section: Protonsupporting

confidence: 72%

“…This is based upon: 1) the relatively high affinity binding of these antibodies to CRK which is relatively unstructured, and 2) the fact that the small tendency of this peptide (in its conjugated state) did not significantly affect 5023A/5025A binding to the peptide. This is also consistent with the fact that the full epitopes recognized by these antibodies include most, but not all of the residues in the GPGR sequence (47,51) and hence adoption of any particular structure in the GPGR region may be of less consequence to antibody binding. Also, since CRK lacks significant folded structure, the most likely scheme of peptide binding by antibodies 5023A and 5025A must involve an induced fit of this peptide to the binding sites of both antibodies.…”

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledsupporting

confidence: 65%

“…Correspondingly, the relative errors obtained for the 5025A K Aff values were all lower compared with those of 5023A. This discrepancy can be rationalized on the basis of differences in the 5023A and 5025A antigenic epitopes (47,51 . Since all the 5025A epitope residues are distant from both peptide coupling sites, heterogeneous coupling effects upon 5025A binding to the conjugate were probably much less significant.…”

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 81%

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The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Wu¹,

MacKenzie²,

Durda³

et al. 2000

Journal of Biological Chemistry

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The structural and antigenic properties of a peptide ("CRK") derived from the V3 loop of HIV-1 gp120 protein were studied using NMR and SPR techniques. The sequence of CRK corresponds to the central portion of the V3 loop containing the highly conserved "GPGR" residue sequence. Although the biological significance of this conserved sequence is unknown, the adoption of conserved secondary structure (type II ␤-turn) in this region has been proposed. The tendency of CRK (while free or conjugated to protein), to adopt such structure and the influence of such structure upon CRK antigenicity were investigated by NMR and SPR, respectively. Regardless of conjugation, CRK is conformationally averaged in solution but a weak tendency of the CRK "GPGR" residues to adopt a ␤-turn conformation was observed after conjugation. The influence of GPGR structure upon CRK antigenicity was investigated by measuring the affinities of two cognate antibodies: "5023A" and "5025A," for CRK, protein-conjugated CRK and gp120 protein. Each antibody bound to all the antigens with nearly the same affinity. From these data, it appears that: (a) antibody binding most likely involves an induced fit of the peptide and (b) the gp120 V3 loop is probably conformationally heterogeneous. Since 5023A and 5025A are HIV-1 neutralizing antibodies, neutralization in these cases appears to be independent of adopted GPGR ␤-turn structure. The principal neutralizing determinant (PND)1 of HIV-1 has been mapped to the third hypervariable (V3) loop of the HIV-1 envelope protein, gp120 (1). PND-derived peptides are used as immunogens to elicit antibodies that possess HIV-1 virus neutralization capabilities (2, 3). The binding of neutralizing antibodies blocks virus entry into the host cell but does not prevent binding of HIV-1 to its primary cell receptor protein, CD4 (4, 5). Although the V3 loop represents an important target for the development of vaccines against AIDS, its high sequence variability also makes it a very problematic one (6). Nonetheless, the occurrence of the highly conserved residue sequence, "GPGR," at the tip of the V3 loop has raised the possibility that these residues make up a conserved secondary structural element in gp120. The function of such a structural element, if one exists, is presently unknown, however. The precise predicted secondary structure adopted by the GPGR residues is a type II ␤-turn (6, 7).In order to determine whether the conserved GPGR sequence confers certain secondary structural tendencies upon this region of the V3 loop, numerous NMR studies were conducted upon a variety of V3 loop-derived peptides (8 -21). These peptides were shown to have only low density populations of folded structure and to be conformationally averaged in solution. Despite the report of a "core" gp120 protein complex crystal structure, this complex was prepared using a form of gp120 which lacked most of the hypervariable loops including V3 (22). Information regarding the actual three-dimensional structure of the V3 loop in native gp120 is theref...

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Section: Protonsupporting

confidence: 72%

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledsupporting

confidence: 65%

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 81%

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The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Wu¹,

MacKenzie²,

Durda³

et al. 2000

Journal of Biological Chemistry

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“…Thus, some aa contained within a sequence present a greater contribution than others to the reactive epitope, and change of a single aa can be sufficient to completely abolish antibody recognition. This has been verified for V3 [15,[21][22][23]351. For example, change of P318 to Q almost completely abolishes the binding and neutralizing activity of monoclonal antibody 0.5/I [21] and change of FR3** to L increases resistance to neutralization by soluble CD4 [231.…”

Section: Discussionmentioning

confidence: 61%

“…For example, when considering anti-V3 neutralizing human monoclonal antibodies 'the higher the affinity for V3,, the less monoclonal antibody is needed to neutralize the virus', and only antibodies with high affinities ( < 1 x 10e6 M) are able to neutralize in vitro [15,31] or to apparently prevent HIV-I vertical transmission [36].…”

Section: Discussionmentioning

confidence: 99%

Effect of sialic acid removal on the antibody response to the third variable domain of human immunodeficiency virus type‐1 envelope glycoprotein

et al. 1994

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AhstraetThe gp160 envelope glycoprotein of human immunodeficiency virus type-l (HIV-l) is an essential component of current vaccine trials. The glycans of gp160, part of which are highly sialylated, have been shown to influence gp160 immunogenicity. Here, using a panel of synthetic V3 peptides, we characterized the anti-V3 antibodies generated in rabbits immunized by desialylated recombinant gp160,,. Amino acid residues flanking the GPGR tip of V3 were necessary for the recognition by anti-V3 antibodies raised against either the native or desialylated gp160. Both types of antibodies reacted to V3 peptides of MN and SF2 strains and with a North American/European V3 consensus peptide, while anti-desialylated gpl60,, antibodies reacted in addition to the V3 of CDC4, WMJ2 and NY5 strains. Yet, the V3 peptides did not signiscantly differ in their secondary structure, as determined by circular dichroism. The titer and avidity for V3,, of anti-desialylated gp160,, antibodies were significantly lower than those of anti-native gp160,, which likely accounts for the inability of anti-desialylated gp160, sera to neutralize HIV-1,Kinduced syncytia. These results indicate that V3 immunogenicity may be iduenced by subtle directed changes in the gpl60 glycosylation pattern.

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NMR study and comparison of the antigenic properties of a peptide recognized by two HIV-1 neutralizing antibodies

Tsang

et al. 1997

J. Mol. Recognit.

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Fab-peptide complexes formed between a 15 residue peptide derived from the HIV-1 gp120 V3 loop and two of its cognate monoclonal antibodies, 5023A and 5025A, were studied using isotope-edited solution nuclear magnetic resonance (NMR) techniques. Since these antibodies neutralize HIV-1 virus with different strain specificities, this study was conducted to better understand the nature of these differences. The amide proton and nitrogen NMR resonances of specific residues were used to monitor the backbone of this peptide in these complexes. Three central residues of this peptide ('RAF') were found to be strongly affected by binding to both antibodies. Several other peptide residues were affected by binding to antibody 5023A but not 5025A. The antibody epitopes mapped by NMR are similar to those obtained previously via PEPSCAN at higher pH. One main difference between the PEPSCAN and NMR determined epitopes for 5023A involved two glycine residues of the peptide. By NMR, one of these glycines was more dramatically affected by antibody binding than predicted by PEPSCAN, while the other was much less so.

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Neutralizing activity of anti-peptide antibodies against the principal neutralization domain of human immunodeficiency virus type 1

Cited by 33 publications

References 30 publications

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

The Binding of a Glycoprotein 120 V3 Loop Peptide to HIV-1 Neutralizing Antibodies

Effect of sialic acid removal on the antibody response to the third variable domain of human immunodeficiency virus type‐1 envelope glycoprotein

NMR study and comparison of the antigenic properties of a peptide recognized by two HIV-1 neutralizing antibodies

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