The V1V2 Domain and an N-Linked Glycosylation Site in the V3 Loop of the HIV-1 Envelope Glycoprotein Modulate Neutralization Sensitivity to the Human Broadly Neutralizing Antibody 2G12

Chaillon, Antoine; Braibant, Martine; Moreau, Thierry; Thenin, Suzie; Moreau, Alain; Autran, Brigitte; Barin, Françis

doi:10.1128/jvi.02424-10

Cited by 22 publications

(22 citation statements)

References 40 publications

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“…Neutralization of the BG505 pseudovirus by PGT126, which is closely related to PGT128, is surprising since structural studies of cocrystals formed with PGT128 FAb and an outer domain construct containing a mini-V3 loop (eODmV3) indicate that there is binding to a glycan determinant at position N332 (24) which is absent in BG505. Binding and neutralization of BG505 by PGT126 may be explained by promiscuity of some antibodies (25) or regulation of access to the V3 loop by V1V2 (63). In the current study, we found (Fig.…”

Section: Discussionsupporting

confidence: 77%

Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Hoffenberg

Powell

Carpov

et al. 2013

J Virol

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f ; Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA g Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.

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Section: Discussionsupporting

confidence: 77%

Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Hoffenberg

Powell

Carpov

et al. 2013

J Virol

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“…Previous studies have shown that sequence variation in variable regions 1 and 2 (V1V2) can dramatically impact antibody binding and neutralization (68)(69)(70)(71)(72). Most recently, analyses in RV144 revealed that the level of binding of IgG antibodies to V1V2 correlated inversely with the rate of HIV-1 infection (73) and that there was an increased vaccine efficacy against viruses with genetic signatures in V2 (42).…”

Section: Iii) Distance To Hiv-1 Gag and Pro Of Lai (Alvac-hiv)mentioning

confidence: 99%

Molecular Evolution of the HIV-1 Thai Epidemic between the Time of RV144 Immunogen Selection to the Execution of the Vaccine Efficacy Trial

Kijak

Tovanabutra

Rerks-Ngarm

et al. 2013

J Virol

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The RV144 HIV-1 vaccine trial (Thailand, 2003 to 2009), using immunogens genetically matched to the regional epidemic, demonstrated the first evidence of efficacy for an HIV-1 vaccine. Here we studied the molecular evolution of the HIV-1 epidemic from the time of immunogen selection to the execution of the efficacy trial. We studied HIV-1 genetic diversity among 390 volunteers who were deferred from enrollment in RV144 due to preexisting HIV-1 infection using a multiregion hybridization assay, full-genome sequencing, and phylogenetic analyses. The subtype distribution was 91.7% CRF01_AE, 3.5% subtype B, 4.3% B/CRF01_AE recombinants, and 0.5% dual infections. CRF01_AE strains were 31% more diverse than the ones from the 1990s Thai epidemic. Sixty-nine percent of subtype B strains clustered with the cosmopolitan Western B strains. Ninety-three percent of B/CRF01_AE recombinants were unique; recombination breakpoint analysis showed that these strains were highly embedded within the larger network that integrates recombinants from East/Southeast Asia. Compared to Thai sequences from the early 1990s, the distance to the RV144 immunogens increased 52% to 68% for CRF01_AE Env immunogens and 12% to 29% for subtype B immunogens. Forty-three percent to 48% of CRF01_AE sequences differed from the sequence of the vaccine insert in Env variable region 2 positions 169 and 181, which were implicated in vaccine sieve effects in RV144. In conclusion, compared to the molecular picture at the early stages of vaccine development, our results show an overall increase in the genetic complexity of viruses in the Thai epidemic and in the distance to vaccine immunogens, which should be considered at the time of the analysis of the trial results.

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“…We favor this model because it relies entirely on prior evidence. Additionally, V3 mutations alter sensitivity to 2G12 (38). Moreover, residues 295 and 332 at the V3 border are also targets for autologous NAbs in newly infected individuals (3,39), and terminal mannoses in glycans at N295, N301, and N332 plus nearby V3 amino acids in gp120 JRCSF interact with NMAbs PGT127 and PGT128 from elite neutralizers (2,4).…”

Section: G12 Inhibits Cd4 and Ccr5 Binding And Blocks A Coreceptordementioning

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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The V1V2 Domain and an N-Linked Glycosylation Site in the V3 Loop of the HIV-1 Envelope Glycoprotein Modulate Neutralization Sensitivity to the Human Broadly Neutralizing Antibody 2G12

Cited by 22 publications

References 40 publications

Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Identification of an HIV-1 Clade A Envelope That Exhibits Broad Antigenicity and Neutralization Sensitivity and Elicits Antibodies Targeting Three Distinct Epitopes

Molecular Evolution of the HIV-1 Thai Epidemic between the Time of RV144 Immunogen Selection to the Execution of the Vaccine Efficacy Trial

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

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