scholarly journals CD4 binding site broadly neutralizing antibody selection of HIV-1 escape mutants

2015 ◽  
Vol 96 (7) ◽  
pp. 1899-1905 ◽  
Author(s):  
Hanna Dreja ◽  
Corinna Pade ◽  
Lei Chen ◽  
Áine McKnight
Keyword(s):  
Binding Site ◽  
Neutralizing Antibody ◽  
Cd4 Binding Site ◽  
Escape Mutants ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1 ◽  
Selection Of

scholarly journals Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

2015 ◽  
Vol 112 (38) ◽  
pp. 11947-11952 ◽  
Author(s):  
Jean-Philippe Julien ◽  
Jeong Hyun Lee ◽  
Gabriel Ozorowski ◽  
Yuanzi Hua ◽  
Alba Torrents de la Peña ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Size Exclusion ◽  
Negative Stain ◽  
Clade C ◽  
Exclusion Chromatography ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Negative Stain Electron Microscopy ◽  
Is Design ◽  
Hiv 1

A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.

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 Modeling HIV-1 Within-Host Dynamics After Passive Infusion of the Broadly Neutralizing Antibody VRC01

2021 ◽  
Vol 12 ◽  
Author(s):  
E. Fabian Cardozo-Ojeda ◽  
Alan S. Perelson
Keyword(s):  
Viral Load ◽  
Plasma Viral Load ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Viral Population ◽  
Viral Load Data ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Two Populations ◽  
Hiv 1

VRC01 is a broadly neutralizing antibody that targets the CD4 binding site of HIV-1 gp120. Passive administration of VRC01 in humans has assessed the safety and the effect on plasma viremia of this monoclonal antibody (mAb) in a phase 1 clinical trial. After VRC01 infusion, the plasma viral load in most of the participants was reduced but had particular dynamics not observed during antiretroviral therapy. In this paper, we introduce different mathematical models to explain the observed dynamics and fit them to the plasma viral load data. Based on the fitting results we argue that a model containing reversible Ab binding to virions and clearance of virus-VRC01 complexes by a two-step process that includes (1) saturable capture followed by (2) internalization/degradation by phagocytes, best explains the data. This model predicts that VRC01 may enhance the clearance of Ab-virus complexes, explaining the initial viral decay observed immediately after antibody infusion in some participants. Because Ab-virus complexes are assumed to be unable to infect cells, i.e., contain neutralized virus, the model predicts a longer-term viral decay consistent with that observed in the VRC01 treated participants. By assuming a homogeneous viral population sensitive to VRC01, the model provides good fits to all of the participant data. However, the fits are improved by assuming that there were two populations of virus, one more susceptible to antibody-mediated neutralization than the other.

scholarly journals A1 The role of virus-antibody co-evolution in the development of a V3-glycan-directed HIV-1 broadly neutralizing antibody lineage

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
D Kitchin ◽  
J Bhiman ◽  
D Mvududu ◽  
B Oosthuysen ◽  
B Lambson ◽  
...  
Keyword(s):  
Deep Sequencing ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Viral Escape ◽  
Sequencing Data ◽  
Virus Antibody ◽  
Escape Mutants ◽  
Broadly Neutralizing Antibody ◽  
Hiv Envelope ◽  
Hiv 1

Abstract Broadly neutralizing antibodies (bNAbs) are essential for a preventative HIV-1 vaccine but have not been elicited through vaccination. bNAbs develop in 20–30 per cent of HIV-1 infections and often target the V3-glycan epitope of the HIV envelope protein (Env). In these individuals, virus-antibody co-evolution is thought to drive the maturation of antibody lineages to neutralization breadth. We used deep sequencing of env genes and antibody transcripts from fourteen time points spanning the first 3 years of infection to characterize the virus-antibody co-evolution in donor CAP255 who developed V3-glycan-specific bNAbs. Sequencing and cloning of env genes, followed by neutralization assays, were used to identify Env mutations associated with neutralization escape from two bNAbs (CAP255.G3 and CAP255.C5) isolated at 149 weeks post-infection (wpi). Sequencing data indicated that CAP255 was co-infected by three related viral variants, all of which had an intact N332 glycan, which persisted in > 90 per cent of later viruses. A recombinant V3-region became fixed from 8 wpi, conferring slight neutralization resistance to CAP255.G3/C5 and other V3-glycan bNAbs. Later, T415R/K substitutions in V4 emerged by 51 wpi and were associated with complete viral escape from CAP255.G3/C5, though not from the polyclonal plasma response. All 93-week and later Envs were resistant to CAP255.G3/C5 and V3-glycan bNAb PGT135. Viral escape by 51 wpi suggested that the CAP255 bNAbs arose earlier, driving escape, but persisted to 149 weeks. This was supported by preliminary deep sequencing of the antibody repertoire that indicated bNAb lineage members were already present in the plasma at 39 wpi. Escape from V3-glycan bNAbs via T415R/K mutations have not previously been shown, suggesting a novel mode of recognition within the V3-glycan supersite. Further work will focus on identifying the bNAb-initiating Env and intermediate bNAb lineage members that were capable of engaging contemporaneous Env neutralization escape mutants. Characterization of Envs that engaged bNAb precursors, as well as those that selected for broader members of the bNAb lineage, will inform the design of immunogens capable of eliciting V3-glycan bNAbs in a novel HIV-1 vaccine regimen.

scholarly journals Effects of partially dismantling the CD4 binding site glycan fence of HIV-1 Envelope glycoprotein trimers on neutralizing antibody induction

Virology ◽  
2017 ◽  
Vol 505 ◽  
pp. 193-209 ◽  
Author(s):  
Ema T. Crooks ◽  
Keiko Osawa ◽  
Tommy Tong ◽  
Samantha L. Grimley ◽  
Yang D. Dai ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibody ◽  
Cd4 Binding Site ◽  
Antibody Induction ◽  
Hiv 1

Isolation and characterization of a novel neutralizing antibody targeting the CD4-binding site of HIV-1 gp120

2016 ◽  
Vol 132 ◽  
pp. 252-261 ◽  
Author(s):  
Yuanyuan Qiao ◽  
Lai Man ◽  
Zonglin Qiu ◽  
Lingli Yang ◽  
Youxiang Sun ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibody ◽  
Isolation And Characterization ◽  
Cd4 Binding Site ◽  
Antibody Targeting ◽  
Hiv 1

scholarly journals Polyclonal Broadly Neutralizing Antibody Activity Characterized by CD4 Binding Site and V3-Glycan Antibodies in a Subset of HIV-1 Virus Controllers

2021 ◽  
Vol 12 ◽  
Author(s):  
Tinashe E. Nyanhete ◽  
Robert J. Edwards ◽  
Celia C. LaBranche ◽  
Katayoun Mansouri ◽  
Amanda Eaton ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibodies ◽  
Humoral Response ◽  
Neutralizing Antibody ◽  
Small Subset ◽  
Antibody Activity ◽  
Viral Loads ◽  
Immune Pressure ◽  
Cd4 Binding Site ◽  
Hiv 1

Broadly neutralizing antibodies (bNAbs), known to mediate immune control of HIV-1 infection, only develop in a small subset of HIV-1 infected individuals. Despite being traditionally associated with patients with high viral loads, bNAbs have also been observed in therapy naïve HIV-1+ patients naturally controlling virus replication [Virus Controllers (VCs)]. Thus, dissecting the bNAb response in VCs will provide key information about what constitutes an effective humoral response to natural HIV-1 infection. In this study, we identified a polyclonal bNAb response to natural HIV-1 infection targeting CD4 binding site (CD4bs), V3-glycan, gp120-gp41 interface and membrane-proximal external region (MPER) epitopes on the HIV-1 envelope (Env). The polyclonal antiviral antibody (Ab) response also included antibody-dependent cellular phagocytosis of clade AE, B and C viruses, consistent with both the Fv and Fc domain contributing to function. Sequence analysis of envs from one of the VCs revealed features consistent with potential immune pressure and virus escape from V3-glycan targeting bNAbs. Epitope mapping of the polyclonal bNAb response in VCs with bNAb activity highlighted the presence of gp120-gp41 interface and CD4bs antibody classes with similar binding profiles to known potent bNAbs. Thus, these findings reveal the induction of a broad and polyfunctional humoral response in VCs in response to natural HIV-1 infection.

scholarly journals A New Glycan-Dependent CD4-Binding Site Neutralizing Antibody Exerts Pressure on HIV-1 In Vivo

2015 ◽  
Vol 11 (10) ◽  
pp. e1005238 ◽  
Author(s):  
Natalia T. Freund ◽  
Joshua A. Horwitz ◽  
Lilian Nogueira ◽  
Stuart A. Sievers ◽  
Louise Scharf ◽  
...  
Keyword(s):  
Binding Site ◽  
Neutralizing Antibody ◽  
Cd4 Binding Site ◽  
Hiv 1

scholarly journals Validation of a Triplex Pharmacokinetic Assay for Simultaneous Quantitation of HIV-1 Broadly Neutralizing Antibodies PGT121, PGDM1400, and VRC07-523-LS

2021 ◽  
Vol 12 ◽  
Author(s):  
Martina S. Wesley ◽  
Kelvin T. Chiong ◽  
Kelly E. Seaton ◽  
Christine A. Arocena ◽  
Sheetal Sawant ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Testing Method ◽  
Cd4 Binding Site ◽  
Broadly Neutralizing Antibody ◽  
Effective Doses ◽  
Pharmacokinetic Assay ◽  
Hiv 1

The outcome of the recent Antibody Mediated Prevention (AMP) trials that tested infusion of the broadly neutralizing antibody (bnAb) VRC01 provides proof of concept for blocking infection from sensitive HIV-1 strains. These results also open up the possibility that triple combinations of bnAbs such as PGT121, PGDM1400, as well as long-lasting LS variants such as VRC07-523 LS, have immunoprophylactic potential. PGT121 and PGDM1400 target the HIV-1 V3 and V2 glycan regions of the gp120 envelope protein, respectively, while VRC07-523LS targets the HIV-1 CD4 binding site. These bnAbs demonstrate neutralization potency and complementary breadth of HIV-1 strain coverage. An important clinical trial outcome is the accurate measurement of in vivo concentrations of passively infused bnAbs to determine effective doses for therapy and/or prevention. Standardization and validation of this testing method is a key element for clinical studies as is the ability to simultaneously detect multiple bnAbs in a specific manner. Here we report the development of a sensitive, specific, accurate, and precise multiplexed microsphere-based assay that simultaneously quantifies the respective physiological concentrations of passively infused bnAbs in human serum to ultimately define the threshold needed for protection from HIV-1 infection.

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