scholarly journals Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5

2019 ◽  
Vol 203 (12) ◽  
pp. 3268-3281 ◽  
Author(s):  
Joel Finney ◽  
Guang Yang ◽  
Masayuki Kuraoka ◽  
Shengli Song ◽  
Takuya Nojima ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

scholarly journals Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes

2019 ◽  
Vol 216 (10) ◽  
pp. 2331-2347 ◽  
Author(s):  
Tara Bancroft ◽  
Blair L. DeBuysscher ◽  
Connor Weidle ◽  
Allison Schwartz ◽  
Abigail Wall ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Subunit Vaccines ◽  
Human B Cells ◽  
Immunodeficiency Virus ◽  
Protective Antibodies ◽  
Broadly Neutralizing Antibody ◽  
Precursor B Cells ◽  
Hiv 1

Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells expressing B cell receptors with similarity to iglb12. Immunization with a multimerized version of this anti-idiotype induced the proliferation of transgenic murine B cells expressing the iglb12 heavy chain in vivo, despite the presence of deletion and anergy within this population. Together, our data indicate that anti-idiotypes are a valuable tool for the study and induction of potentially protective antibodies.

scholarly journals HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

Science ◽  
2016 ◽  
Vol 351 (6280) ◽  
pp. 1458-1463 ◽  
Author(s):  
J. G. Jardine ◽  
D. W. Kulp ◽  
C. Havenar-Daughton ◽  
A. Sarkar ◽  
B. Briney ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody ◽  
Precursor B Cells ◽  
Hiv 1

scholarly journals Myomedin scaffold variants targeted to 10E8 HIV-1 broadly neutralizing antibody mimic gp41 epitope and elicit HIV-1 virus-neutralizing sera in mice

Virulence ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 1271-1287
Author(s):  
Milan Kuchař ◽  
Petr Kosztyu ◽  
Veronika Daniel Lišková ◽  
Jiří Černý ◽  
Hana Petroková ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

scholarly journals Differences in the Binding Affinity of an HIV-1 V2 Apex-Specific Antibody for the SIVsmm/macEnvelope Glycoprotein Uncouple Antibody-Dependent Cellular Cytotoxicity from Neutralization

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Benjamin von Bredow ◽  
Raiees Andrabi ◽  
Michael Grunst ◽  
Andres G. Grandea ◽  
Khoa Le ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Specific Antibody ◽  
Neutralizing Antibody ◽  
Glycosylation Site ◽  
Antibody Binding ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibody ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTAs a consequence of their independent evolutionary origins in apes and Old World monkeys, human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses of the SIVsmm/maclineage express phylogenetically and antigenically distinct envelope glycoproteins. Thus, HIV-1 Env-specific antibodies do not typically cross-react with the Env proteins of SIVsmm/macisolates. Here we show that PGT145, a broadly neutralizing antibody to a quaternary epitope at the V2 apex of HIV-1 Env, directs the lysis of SIVsmm/mac-infected cells by antibody-dependent cellular cytotoxicity (ADCC) but does not neutralize SIVsmm/macinfectivity. Amino acid substitutions in the V2 loop of SIVmac239 corresponding to the epitope for PGT145 in HIV-1 Env modulate sensitivity to this antibody. Whereas a substitution in a conserved N-linked glycosylation site (N171Q) eliminates sensitivity to ADCC, a lysine-to-serine substitution in this region (K180S) increases ADCC and renders the virus susceptible to neutralization. These differences in function correlate with an increase in the affinity of PGT145 binding to Env on the surface of virus-infected cells and to soluble Env trimers. To our knowledge, this represents the first instance of an HIV-1 Env-specific antibody that cross-reacts with SIVsmm/macEnv and illustrates how differences in antibody binding affinity for Env can differentiate sensitivity to ADCC from neutralization.IMPORTANCEHere we show that PGT145, a potent broadly neutralizing antibody to HIV-1, directs the lysis of SIV-infected cells by antibody-dependent cellular cytotoxicity but does not neutralize SIV infectivity. This represents the first instance of cross-reactivity of an HIV-1 Env-specific antibody with SIVsmm/macEnv and reveals that antibody binding affinity can differentiate sensitivity to ADCC from neutralization.

scholarly journals Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention

2020 ◽  
Vol 38 (1) ◽  
pp. 673-703 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Kshitij Wagh ◽  
Bette Korber ◽  
Dan H. Barouch
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Aids Pandemic ◽  
Broadly Neutralizing Antibody ◽  
Early Phase Clinical Trials ◽  
Hiv 1 ◽  
Review Current

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.

scholarly journals A Glycoconjugate Antigen Based on the Recognition Motif of a Broadly Neutralizing Human Immunodeficiency Virus Antibody, 2G12, Is Immunogenic but Elicits Antibodies Unable To Bind to the Self Glycans of gp120

2008 ◽  
Vol 82 (13) ◽  
pp. 6359-6368 ◽  
Author(s):  
Rena D. Astronomo ◽  
Hing-Ken Lee ◽  
Christopher N. Scanlan ◽  
Ralph Pantophlet ◽  
Cheng-Yuan Huang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibody ◽  
Humoral Immune ◽  
Aids Vaccine ◽  
Humoral Immune Responses ◽  
Copy Numbers ◽  
Immunodeficiency Virus ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

ABSTRACT The glycan shield of human immunodeficiency virus type 1 (HIV-1) gp120 contributes to viral evasion from humoral immune responses. However, the shield is recognized by the HIV-1 broadly neutralizing antibody (Ab), 2G12, at a relatively conserved cluster of oligomannose glycans. The discovery of 2G12 raises the possibility that a carbohydrate immunogen may be developed that could elicit 2G12-like neutralizing Abs and contribute to an AIDS vaccine. We have previously dissected the fine specificity of 2G12 and reported that the synthetic tetramannoside (Man4) that corresponds to the D1 arm of Man9GlcNAc2 inhibits 2G12 binding to gp120 as efficiently as Man9GlcNAc2 itself, indicating the potential use of Man4 as a building block for creating immunogens. Here, we describe the development of neoglycoconjugates displaying variable copy numbers of Man4 on bovine serum albumin (BSA) molecules by conjugation to Lys residues. The increased valency enhances the apparent affinity of 2G12 for Man4 up to a limit which is achieved at ∼10 copies per BSA molecule, beyond which no further enhancement is observed. Immunization of rabbits with BSA-(Man4)14 elicits significant serum Ab titers to Man4. However, these Abs are unable to bind gp120. Further analysis reveals that the elicited Abs bind a variety of unbranched and, to a lesser extent, branched Man9 derivatives but not natural N-linked oligomannose containing the chitobiose core. These results suggest that Abs can be readily elicited against the D1 arm; however, potential differences in the presentation of Man4 on neoglycoconjugates, compared to glycoproteins, poses challenges for eliciting anti-mannose Abs capable of cross-reacting with gp120 and HIV-1.

scholarly journals HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility

2019 ◽  
Vol 94 (2) ◽  
Author(s):  
Ludy Registre ◽  
Yvetane Moreau ◽  
Sila Toksoz Ataca ◽  
Surya Pulukuri ◽  
Timothy J. Henrich ◽  
...  
Keyword(s):  
Homology Modeling ◽  
Neutralizing Antibody ◽  
V3 Loop ◽  
Plasma Viremia ◽  
Neutralization Sensitivity ◽  
Variable Loop ◽  
Ccr5 Receptor ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1 ◽  
Homology Models

ABSTRACT In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence. The presence of less neutralization-susceptible strains prior to treatment decreases the efficacy of these antibody-based treatments, but neutralization sensitivity often cannot be predicted by sequence analysis alone. We found that phenotypically confirmed CXCR4-utilizing strains are less neutralization sensitive, especially to variable loop 3 (V3 loop)-directed bnAbs, than exclusively CCR5-utilizing strains in some, but not all, cases. Homology modeling suggested that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains, although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. Homology modeling also showed that among some, but not all, envelopes with decreased neutralization sensitivity, V1 loop orientation interfered with V3 loop-directed bnAb binding. Thus, there are likely different structural reasons for the coreceptor usage restriction and the different bnAb susceptibilities. Importantly, we show that individuals harboring envelopes with higher likelihood of using CXCR4 or greater predicted V1 loop interference have faster virus rebound and a lower maximum decrease in plasma viremia, respectively, after treatment with a V3 loop bnAb. Knowledge of receptor usage and homology models may be useful in developing future algorithms that predict treatment efficacy with V3 loop bnAbs. IMPORTANCE The efficacy of HIV-1 broadly neutralizing antibody (bnAb) therapies may be compromised by the preexistence of less susceptible variants. Sequence-based methods are needed to predict pretreatment variants’ neutralization sensitivities. HIV-1 strains that exclusively use the CXCR4 receptor rather than the CCR5 receptor are less neutralization susceptible, especially to variable loop 3 (V3 loop) bnAbs in some, but not all, instances. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Homology modeling predicts that contact between the envelope V1 loop and the antibody impacts V3 loop bnAb susceptibility in some cases. Among pretreatment envelopes, increased probability of using CXCR4 and greater predicted V1 interference are associated with faster virus rebound and a smaller decrease in the plasma virus level, respectively, after V3 loop bnAb treatment. Receptor usage information and homology models may be useful for predicting V3 loop bnAb therapy efficacy.

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