The principal neutralizing determinant of HIV‐1 located in V3 of gp120 forms a 12‐residue loop by internal hydrophobic interactions

Zvi, Anat; Kustanovich, I. M.; Hayek, Yehezkiel; Matsushita, Shuzo; Anglister, Jacob

doi:10.1016/0014-5793(95)00669-z

Cited by 19 publications

(24 citation statements)

References 19 publications

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“…Proline residues often have significant consequences regarding local secondary structure (31,33). Variations in residues flanking the tip of the V3 loop are known to affect conformation (53,54). The synthetic R2 V3 35-mer peptide was much less soluble in aqueous solution than other peptides, consistent with the possibility that the conformation of the peptide was significantly altered by the 313-4PM/HI and/or 325Q/D mutation.…”

Section: Discussionmentioning

confidence: 87%

A Variable Region 3 (V3) Mutation Determines a Global Neutralization Phenotype and CD4-Independent Infectivity of a Human Immunodeficiency Virus Type 1 Envelope Associated with a Broadly Cross-Reactive, Primary Virus-Neutralizing Antibody Response

Zhang¹,

Bouma²,

Park³

et al. 2002

J Virol

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The human serum human immunodeficiency virus type 1 (HIV-1)-neutralizing serum 2 (HNS2) neutralizes many primary isolates of different clades of HIV-1, and virus expressing envelope from the same donor, clone R2, is neutralized cross-reactively by HIV-immune human sera. The basis for this cross-reactivity was investigated. It was found that a rare mutation in the proximal limb of variable region 3 (V3), 313-4 PM, caused virus pseudotyped with the R2 envelope to be highly sensitive to neutralization by monoclonal antibodies (MAbs) directed against conformation-sensitive epitopes at the tip of the V3 loop, such as 19b, and moderately sensitive to MAbs against CD4 binding site (CD4bs) and CD4-induced (CD4i) epitopes, soluble CD4 (sCD4), and HNS2. In addition, introduction of this sequence by mutagenesis caused enhanced sensitivity to neutralization by 19b, anti-CD4i MAb, and HNS2 in three other primary HIV-1 envelopes and by anti-CD4bs MAb and sCD4 in one of the three. The 313-4 PM sequence also conferred increased infectivity for CD4 ؉ CCR5 ؉ cells and the ability to infect CCR5 ؉ cells upon all of these four and two of these four HIV-1 envelopes, respectively. Neutralization of R2 by HNS2 was substantially inhibited by the cyclized R2 V3 35-mer synthetic peptide. Similarly, the peptide also had some lesser efficacy in blocking neutralization of R2 by other sera or of neutralization of other primary viruses by HNS2. Together, these results indicate that the unusual V3 mutation in the R2 clone accounts for its uncommon neutralization sensitivity phenotype and its capacity to mediate CD4-independent infection, both of which could relate to immunogenicity and the neutralizing activity of HNS2. This is also the first primary HIV-1 isolate envelope glycoprotein found to be competent for CD4-independent infection.

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Section: Discussionmentioning

confidence: 87%

A Variable Region 3 (V3) Mutation Determines a Global Neutralization Phenotype and CD4-Independent Infectivity of a Human Immunodeficiency Virus Type 1 Envelope Associated with a Broadly Cross-Reactive, Primary Virus-Neutralizing Antibody Response

Zhang¹,

Bouma²,

Park³

et al. 2002

J Virol

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“…According to the above data, this 12-residue with IRIQRGPGRAFV sequence, in a Fab complex, seemed to form a loop, even in the absence of the disulfide bridge between the two cysteine residues, which exists in native molecules or formed synthetically in previously studied 36-residue or shorter V3 peptides [91]. These Il4/Ile6-Val15 hydrophobic interactions in RP135a V3 peptide bound to the anti-gp120 antibody 0.5 had not been previously observed, either for other V3 peptides or for the longer RP135 peptides.…”

Section: V3 Conformational Studies In Solution-nmr Spectroscopymentioning

confidence: 86%

“…(2A)), namely RP135a, has been performed by Anglister et al in the mid 90's [91]. In this study, RP135a peptide interacts with the anti-gp120 HIV-1 IIIB neutralizing antibody 0.5 and provides some valuable insights about the: (i) U-like shape of V3 peptides, (ii) interaction of the flanking GPGR fragments and (iii) role of some hydrophobic residues.…”

Section: V3 Conformational Studies In Solution-nmr Spectroscopymentioning

confidence: 93%

“…Until the early 90's, predictions of the conformation of V3 loop were based on a neural network approach which yielded for the 35-residue peptide, a -strand -reverse -turn --strand --helix structure [62]. Experimental evidence in solid state through X ray crystallography [49,63,64,[71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] and in solution using NMR spectroscopy [42,67,[86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103] suggest that predictable conformational features are present in V3-derived peptide epitopes from various HIV-1 strains.…”

Section: V3 Conformational Featuresmentioning

confidence: 99%

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Conformational Properties of HIV-1 gp120/V3 Immunogenic Domains

Galanakis

Spyroulias²,

Rizos³

et al. 2005

CMC

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Infection of target host cells by the human immunodeficiency virus-1 (HIV-1) is a multi-step process involving a series of conformational changes in the viral gp120 and gp41 proteins. Gp120 binding to the main cell receptor, CD4, on the surface of cells expressing this molecule, and interaction with the cell chemokine receptors CCR5 and CXCR4, are among the key events for HIV-1 infection. These steps are crucial for the virus and offer potential therapeutic targets. For this reason, understanding the structure and the physicochemical characteristics of the gp120 in relation to these interactions has drawn much attention. This review article focuses on the biologically important V3 region of the gp120 and summarizes the functional role, the sequence variation and the conformational features of V3 peptides, which are important for co-receptor selectivity, specificity and interaction. Synthetic V3 peptides have been extensively studied by NMR spectroscopy and X-ray crystallography, in solution or in solid state, in their free or bound form, and valuable information was generated with the aim to be exploited in the design of new, effective inhibitors of HIV-1 infection. The features of the potential gp120 interacting sites on the two chemokine co-receptors, CCR5 and CXCR4, are also discussed, and co-receptor blocking molecules under clinical trial are also reported.

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“…Difference spectroscopy using a deuterated three-residue peptide inhibitor of pepsin was applied by Fesik and Zuiderweg [43] to study the conformation of the inhibitor bound to pepsin. We have recently used this approach in our studies of the 0.5/3 antibody in complex with 16-and 18-residue peptides of the V3 loop of HIV-1IIIB [44,45]. To understand the molecular basis of recognition between the antibody and the PND, the solution structure of the free antigenic peptide was studied, the epitope recognized by the neutralizing antibody was mapped, and the structure of the bound peptide within the complex was solved.…”

Section: Introductionmentioning

confidence: 99%

The principal neutralizing determinant of HIV-1IIIB: Conformation of the peptide bound to a neutralizing antibody studied by 2D-NMR

Zvi

Anglister

1998

Lett Pept Sci

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SummaryRP135 is a 24-residue peptide corresponding to the principal neutralizing determinant of the envelope glycoprotein gp120 of the human immunodeficiency virus type 1. We have studied the conformation of RP135 in complex with a neutralizing antibody 0.5/~ raised against gpl20 by 2D NMR spectroscopy. The antigenic determinant recognized by this antibody was mapped using a combination of HOHAHA and ROESY measurements, in which resonances of the Fab and the tightly bound peptide residues are eliminated and the mobile residues of the bound peptide are sequentially assigned. We found that residues Ser 6 -Thr 19 are part of the epitope, while Lys 5 and Ile g~ are at its boundaries. Difference spectroscopy was applied to study the conformation of the bound peptide representing the epitope within the 52 kDa of the Fab complex. Specific residues of the peptide were deuterated or replaced and the difference between the NOESY spectrum of the complex with the unlabeled residue and the NOESY spectrum of the complex with the modified residue revealed the interactions of the labeled residue both within the peptide and with the Fab fragment. A total of 122 distance restraints derived from the difference spectra enabled the calculation of the structure of the bound peptide. The peptide forms a 10-residue loop, while the two segments flanking this loop interact extensively with each other and possibly form anti-parallel/%strands. The loop conformation could be observed due to the unusual large size (17 residues) of the antigenic determinant recognized by 0.5/~.

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The principal neutralizing determinant of HIV‐1 located in V3 of gp120 forms a 12‐residue loop by internal hydrophobic interactions

Cited by 19 publications

References 19 publications

A Variable Region 3 (V3) Mutation Determines a Global Neutralization Phenotype and CD4-Independent Infectivity of a Human Immunodeficiency Virus Type 1 Envelope Associated with a Broadly Cross-Reactive, Primary Virus-Neutralizing Antibody Response

A Variable Region 3 (V3) Mutation Determines a Global Neutralization Phenotype and CD4-Independent Infectivity of a Human Immunodeficiency Virus Type 1 Envelope Associated with a Broadly Cross-Reactive, Primary Virus-Neutralizing Antibody Response

Conformational Properties of HIV-1 gp120/V3 Immunogenic Domains

The principal neutralizing determinant of HIV-1IIIB: Conformation of the peptide bound to a neutralizing antibody studied by 2D-NMR

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