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 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.

scholarly journals Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

2018 ◽  
Vol 93 (4) ◽  
Author(s):  
Yijun Zhang ◽  
James H. Chapman ◽  
Asim Ulcay ◽  
Richard E. Sutton
Keyword(s):  
Binding Site ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Phase Iii ◽  
Broadly Neutralizing Antibodies ◽  
New Drug ◽  
Wide Range ◽  
Cd4 Binding Site ◽  
Hiv 1 ◽  
Prevention And Therapy

ABSTRACTAttachment inhibitor (AI) BMS-626529 (fostemsavir) represents a novel class of antiretrovirals which target human immunodeficiency virus type 1 (HIV-1) gp120 and block CD4-induced conformational changes required for viral entry. It is now in phase III clinical trials and is expected to be approved by the U.S. Food and Drug Administration (FDA) in the near future. Although fostemsavir is very potent against HIVin vitroandin vivo, a number of resistant mutants have already been identified. Broadly neutralizing HIV antibodies (bNAbs) can potently inhibit a wide range of HIV-1 strains by binding to viral Env and are very promising candidates for HIV-1 prevention and therapy. Since both target viral Env to block viral entry, we decided to investigate the relationship between these two inhibitors. Our data show that Env mutants resistant to BMS-626529 retained susceptibility to bNAbs. A single treatment of bNAb NIH45-46G54Wcompletely inhibited the replication of these escape mutants. Remarkable synergy was observed between BMS-626529 and CD4 binding site (CD4bs)-targeting bNAbs in neutralizing HIV-1 strains at low concentrations. This synergistic effect was enhanced against virus harboring mutations conferring resistance to BMS-626529. The mechanistic basis of the observed synergy is likely enhanced inhibition of CD4 binding to the HIV-1 Env trimer by the combination of BMS-626529 and CD4bs-targeting bNAbs. This work highlights the potential for positive interplay between small- and large-molecule therapeutics against HIV entry, which may prove useful as these agents enter clinical use.IMPORTANCEAs the worldwide HIV pandemic continues, there is a continued need for novel drugs and therapies. A new class of drug, the attachment inhibitors, will soon be approved for the treatment of HIV. Broadly neutralizing antibodies are also promising candidates for HIV prevention and therapy. We investigated how this drug might work with these exciting antibodies that are very potent in blocking HIV infection of cells. These antibodies worked against virus known to be resistant to the new drug. In addition, a specific type of antibody worked really well with the new drug in blocking virus infection of cells. This work has implications for both the new drug and the antibodies that are poised to be used against HIV.

scholarly journals Targeting HIV using Structure-Based Rational Design of Antibodies

2014 ◽  
Vol 70 (a1) ◽  
pp. C119-C119
Author(s):  
Ron Diskin ◽  
Johannes Scheid ◽  
Anthony West ◽  
Florian Klein ◽  
Michel Nussenzweig ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Passive Immunization ◽  
Broadly Neutralizing Antibodies ◽  
X Ray Crystallography ◽  
Cd4 Binding Site ◽  
Topical Microbicides ◽  
Anti Hiv ◽  
New Strategies

Isolating and studying broadly anti HIV neutralizing antibodies from infected individuals is a major effort in the combat against HIV. We hope to gain better understanding for vaccine design by elucidating the exact epitope of such antibodies. Furthermore, by providing evermore potent and broadly neutralizing antibodies new strategies like passive immunization or using antibodies as topical microbicides for HIV prevention become feasible. One class of promising antibodies is anti CD4 binding site antibodies. Such antibodies can show exceptional potency and breadth. We used X-ray crystallography to study the structure of NIH45-46, one of the most potent anti CD4 binding site antibodies ever described in complex with gp120, the HIV receptor binding domain. Our structural analysis identified a region in the inner domain of gp120 that is important for the binding and neutralization of NIH45-46 (Diskin et al., 2011). This region is contacted by a four-residue insertion in CDRH3 that does not exist in VRC01, a less potent clonal member of NIH45-46. We further used structure-based rational design to improve NIH45-46. By replacing Gly54 in the CDRH2 with a tryptophan we allowed NIH45-46G54W to bind a unique hydrophobic pocket on the surface of gp120 that is normally accommodating Phe43 of CD4. Remarkably, NIH45-46G54W shows increase both in breadth and potency compared with NIH45-46 (Diskin et al., 2011). We took this approach further and engineered NIH45-46G54W to bind a conserved glycan on gp120. This effort resulted with the most potent and broadly neutralizing anti HIV antibody ever described (Diskin et al., 2013). I will present this work and additional efforts to modify NIH45-46 to accommodate potential escape mutations of HIV.

scholarly journals A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jean-François Bruxelle ◽  
Tess Kirilenko ◽  
Nino Trattnig ◽  
Yiqiu Yang ◽  
Matteo Cattin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Envelope Protein ◽  
Protein Sequence ◽  
Neutralizing Antibodies ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Specific Antibodies ◽  
Strong Binding ◽  
Hiv Envelope ◽  
Hiv 1

AbstractThe occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

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