Inhibition of Virus Attachment to CD4+ Target Cells Is a Major Mechanism of T Cell Line–adapted HIV-1 Neutralization

Ugolini, Sophie; Mondor, Isabelle; Parren, Paul W.H.I.; Burton, Dennis R.; Tilley, Shermaine A.; Klasse, Per Johan; Sattentau, Quentin J.

doi:10.1084/jem.186.8.1287

Cited by 114 publications

(111 citation statements)

References 70 publications

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“…In terms of HIV-1 virus neutralization, the binding of neutralizing antibodies to HIV-1 virus appears to somehow interfere with specific, but still unknown HIV-1 V3 loop binding events that are required for infection (63). While the 5023A and 5025A antibodies are not necessarily representative of all HIV-1 neutralizing antibodies, it appears that their binding to HIV-1 is independent of the particular, folded structure adopted by the V3 loop GPGR residues.…”

Section: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

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: Structural Tendencies Of Uncoupled Versus Bpti-coupledmentioning

confidence: 99%

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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“…Prevention of viral infection by antibodies depends on diverse mechanisms such as prevention of viral attachment to the host cell (1,2), activation of the complement system (3,4), opsonization (5), antibody-dependent cell-mediated cytotoxicity (6,7), and inhibition of the release of daughter viruses from infected cells (8)(9)(10). Such a wide variety of antibody activities are mediated by a generation of various classes of antibody (IgG, IgA, and IgE) besides IgM and IgD through class switch recombination (CSR; 11).…”

Section: Introductionmentioning

confidence: 99%

Unmutated immunoglobulin M can protect mice from death by influenza virus infection

Harada

Muramatsu

Shibata

et al. 2004

International Congress Series

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“…For example, several NMAbs alter conformations of purified gp120 and/or inhibit its interactions with CD4 or coreceptors (5,6), but it is unclear how or whether those effects contribute to neutralization. Indeed, it has been proposed that neutralization might ultimately require secondary processes such as NAb crosslinking, prevention of adsorption, or gp120 shedding (7)(8)(9)(10). A central cause for uncertainty occurs because the infectivity assays required to identify and analyze neutralization have been poorly understood and give discrepant results using identical HIV-1s and NAbs (11)(12)(13).…”

mentioning

confidence: 99%

Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry

Platt

Gomes

Kabat

2012

Proc. Natl. Acad. Sci. U.S.A.

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Despite structural knowledge of broadly neutralizing monoclonal antibodies (NMAbs) complexed to HIV-1 gp120 and gp41 envelope glycoproteins, virus inactivation mechanisms have been difficult to prove, in part because neutralization assays are complex and were previously not understood. Concordant with recent evidence that HIV-1 titers are determined by a race between entry of cell-attached virions and competing inactivation processes, we show that NMAb 2G12, which binds to gp120 N-glycans with α (1, 2)-linked mannose termini and inhibits replication after passive transfer into patients, neutralizes by slowing entry of adsorbed virions. Accordingly, apparent neutralization is attenuated when a kinetically competing virus inactivation pathway is blocked. Moreover, removing 2G12 from media causes its dissociation from virions coupled to accelerated entry and restored infectivity, demonstrating the reversibility of neutralization. A difference between 2G12 dissociation and infectivity recovery rates implies that the inhibited complexes at virus-cell junctions contain several 2G12's that must dissociate before entry commences. Quantitative microscopy of 2G12 binding and dissociation from single virions and studies using a split CCR5 coreceptor suggest that 2G12 competitively inhibits interactions between gp120's V3 loop and the tyrosine sulfate-containing CCR5 amino terminus, thereby reducing assembly of complexes that catalyze entry. These results reveal a unique reversible kinetic mechanism for neutralization by an antibody that binds near a critical V3 region in the glycan shield of gp120.

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Inhibition of Virus Attachment to CD4+ Target Cells Is a Major Mechanism of T Cell Line–adapted HIV-1 Neutralization

Cited by 114 publications

References 70 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

Unmutated immunoglobulin M can protect mice from death by influenza virus infection

Kinetic mechanism for HIV-1 neutralization by antibody 2G12 entails reversible glycan binding that slows cell entry

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