scholarly journals Correction for Ingale et al., Hyperglycosylated Stable Core Immunogens Designed To Present the CD4 Binding Site Are Preferentially Recognized by Broadly Neutralizing Antibodies

2015 ◽  
Vol 89 (12) ◽  
pp. 6526-6526
Author(s):  
Jidnyasa Ingale ◽  
Karen Tran ◽  
Leopold Kong ◽  
Barna Dey ◽  
Krisha McKee ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Stable Core

scholarly journals Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

2012 ◽  
Vol 209 (8) ◽  
pp. 1469-1479 ◽  
Author(s):  
Florian Klein ◽  
Christian Gaebler ◽  
Hugo Mouquet ◽  
D. Noah Sather ◽  
Clara Lehmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Conformational Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Capture Method ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Viral Isolates

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

scholarly journals Selection Pressure on HIV-1 Envelope by Broadly Neutralizing Antibodies to the Conserved CD4-Binding Site

2012 ◽  
Vol 86 (10) ◽  
pp. 5844-5856 ◽  
Author(s):  
X. Wu ◽  
C. Wang ◽  
S. O'Dell ◽  
Y. Li ◽  
B. F. Keele ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Selection Pressure ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer

2021 ◽  
Author(s):  
Zhi Yang ◽  
Kim-Marie A. Dam ◽  
Michael D. Bridges ◽  
Magnus A.G. Hoffmann ◽  
Andrew T. DeLaitsch ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Resonance Spectroscopy ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
Double Electron ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Double Electron Electron Resonance ◽  
Hiv 1

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterized Ab1303 and Ab1573, neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding was observed only when Env trimers were not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures showed that both antibodies recognized the CD4bs on Env trimer with an occluded-open conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation included outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, did not exhibit V1V2 displacement, co-receptor binding site exposure, or a 4-stranded gp120 bridging sheet. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggested an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.

scholarly journals Sequences in Glycoprotein gp41, the CD4 Binding Site, and the V2 Domain Regulate Sensitivity and Resistance of HIV-1 to Broadly Neutralizing Antibodies

2012 ◽  
Vol 86 (22) ◽  
pp. 12105-12114 ◽  
Author(s):  
S. M. O'Rourke ◽  
B. Schweighardt ◽  
P. Phung ◽  
K. A. Mesa ◽  
A. L. Vollrath ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Glycoprotein Gp41 ◽  
Hiv 1

scholarly journals Structural survey of HIV-1-neutralizing antibodies targeting Env trimer delineates epitope categories and suggests vaccine templates

2018 ◽  
Author(s):  
Gwo-Yu Chuang ◽  
Jing Zhou ◽  
Reda Rawi ◽  
Chen-Hsiang Shen ◽  
Zizhang Sheng ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Immune Recognition ◽  
Broadly Neutralizing Antibodies ◽  
Independent Sequence ◽  
Cd4 Binding Site ◽  
Hiv 1 ◽  
Cell Ontogeny

HIV-1 broadly neutralizing antibodies are desired for their therapeutic potential and as templates for vaccine design. Such antibodies target the HIV-1-envelope (Env) trimer, which is shielded from immune recognition by extraordinary glycosylation and sequence variability. Recognition by broadly neutralizing antibodies thus provides insight into how antibody can bypass these immune-evasion mechanisms. Remarkably, antibodies neutralizing >25% of HIV-1 strains have now been identified that recognize all major exposed surfaces of the prefusion-closed Env trimer. Here we analyzed all 206 broadly neutralizing antibody-HIV-1 Env complexes in the PDB with resolution suitable to define their interaction chemistries. These segregated into 20 antibody classes based on ontogeny and recognition, and into 6 epitope categories (V1V2, glycan-V3, CD4-binding site, silent face center, fusion peptide, and subunit interface) based on recognized Env residues. We measured antibody neutralization on a 208-isolate panel and analyzed features of paratope and B cell ontogeny. The number of protruding loops, CDR H3 length, and level of somatic hypermutation for broadly HIV-1 neutralizing antibodies were significantly higher than for a comparison set of non-HIV-1 antibodies. For epitope, the number of independent sequence segments was higher (P < 0.0001), as well as the glycan component surface area (P = 0.0005). Based on B cell ontogeny, paratope, and breadth, the CD4-binding site antibody IOMA appeared to be a promising candidate for lineage-based vaccine design. In terms of epitope-based vaccine design, antibody VRC34.01 had few epitope segments, low epitope-glycan content, and high epitope-conformational variability, which may explain why VRC34.01-based design is yielding promising vaccine results.

scholarly journals Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies

2013 ◽  
Vol 210 (4) ◽  
pp. 655-663 ◽  
Author(s):  
Andrew T. McGuire ◽  
Sam Hoot ◽  
Anita M. Dreyer ◽  
Adriana Lippy ◽  
Andrew Stuart ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Variable Region ◽  
Neutralizing Antibody ◽  
Glycosylation Site ◽  
Affinity Maturation ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Hiv Envelope

Broadly neutralizing antibodies (bnAbs) against HIV are believed to be a critical component of the protective responses elicited by an effective HIV vaccine. Neutralizing antibodies against the evolutionarily conserved CD4-binding site (CD4-BS) on the HIV envelope glycoprotein (Env) are capable of inhibiting infection of diverse HIV strains, and have been isolated from HIV-infected individuals. Despite the presence of anti–CD4-BS broadly neutralizing antibody (bnAb) epitopes on recombinant Env, Env immunization has so far failed to elicit such antibodies. Here, we show that Env immunogens fail to engage the germline-reverted forms of known bnAbs that target the CD4-BS. However, we found that the elimination of a conserved glycosylation site located in Loop D and two glycosylation sites located in variable region 5 of Env allows Env-binding to, and activation of, B cells expressing the germline-reverted BCRs of two potent broadly neutralizing antibodies, VRC01 and NIH45-46. Our results offer a possible explanation as to why Env immunogens have been ineffective in stimulating the production of such bNAbs. Importantly, they provide key information as to how such immunogens can be engineered to initiate the process of antibody-affinity maturation against one of the most conserved Env regions.

scholarly journals Structure of an N276-Dependent HIV-1 Neutralizing Antibody Targeting a Rare V5 Glycan Hole Adjacent to the CD4 Binding Site

2016 ◽  
Vol 90 (22) ◽  
pp. 10220-10235 ◽  
Author(s):  
Constantinos Kurt Wibmer ◽  
Jason Gorman ◽  
Colin S. Anthony ◽  
Nonhlanhla N. Mkhize ◽  
Aliaksandr Druz ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Deep Sequencing ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Specific Antibodies ◽  
Founder Virus ◽  
Cd4 Binding Site ◽  
Hiv 1 ◽  
Transmitted Founder Virus

ABSTRACT All HIV-1-infected individuals develop strain-specific neutralizing antibodies to their infecting virus, which in some cases mature into broadly neutralizing antibodies. Defining the epitopes of strain-specific antibodies that overlap conserved sites of vulnerability might provide mechanistic insights into how broadly neutralizing antibodies arise. We previously described an HIV-1 clade C-infected donor, CAP257, who developed broadly neutralizing plasma antibodies targeting an N276 glycan-dependent epitope in the CD4 binding site. The initial CD4 binding site response potently neutralized the heterologous tier 2 clade B viral strain RHPA, which was used to design resurfaced gp120 antigens for single-B-cell sorting. Here we report the isolation and structural characterization of CAP257-RH1, an N276 glycan-dependent CD4 binding site antibody representative of the early CD4 binding site plasma response in donor CAP257. The cocrystal structure of CAP257-RH1 bound to RHPA gp120 revealed critical interactions with the N276 glycan, loop D, and V5, but not with aspartic acid 368, similarly to HJ16 and 179NC75. The CAP257-RH1 monoclonal antibody was derived from the immunoglobulin-variable IGHV3-33 and IGLV3-10 genes and neutralized RHPA but not the transmitted/founder virus from donor CAP257. Its narrow neutralization breadth was attributed to a binding angle that was incompatible with glycosylated V5 loops present in almost all HIV-1 strains, including the CAP257 transmitted/founder virus. Deep sequencing of autologous CAP257 viruses, however, revealed minority variants early in infection that lacked V5 glycans. These glycan-free V5 loops are unusual holes in the glycan shield that may have been necessary for initiating this N276 glycan-dependent CD4 binding site B-cell lineage. IMPORTANCE The conserved CD4 binding site on gp120 is a major target for HIV-1 vaccine design, but key events in the elicitation and maturation of different antibody lineages to this site remain elusive. Studies have shown that strain-specific antibodies can evolve into broadly neutralizing antibodies or in some cases act as helper lineages. Therefore, characterizing the epitopes of strain-specific antibodies may help to inform the design of HIV-1 immunogens to elicit broadly neutralizing antibodies. In this study, we isolate a narrowly neutralizing N276 glycan-dependent antibody and use X-ray crystallography and viral deep sequencing to describe how gp120 lacking glycans in V5 might have elicited these early glycan-dependent CD4 binding site antibodies. These data highlight how glycan holes can play a role in the elicitation of B-cell lineages targeting the CD4 binding site.

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