scholarly journals Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies

2013 ◽  
Vol 210 (2) ◽  
pp. 241-256 ◽  
Author(s):  
Guang Yang ◽  
T. Matt Holl ◽  
Yang Liu ◽  
Yi Li ◽  
Xiaozhi Lu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Direct Evidence ◽  
Hydrophobic Interactions ◽  
Serum Antibody ◽  
Immunological Tolerance ◽  
Human Monoclonal Antibodies ◽  
Central Tolerance ◽  
4E10 Epitope ◽  
Humoral Responses ◽  
Hiv 1

Many human monoclonal antibodies that neutralize multiple clades of HIV-1 are polyreactive and bind avidly to mammalian autoantigens. Indeed, the generation of neutralizing antibodies to the 2F5 and 4E10 epitopes of HIV-1 gp41 in man may be proscribed by immune tolerance because mice expressing the VH and VL regions of 2F5 have a block in B cell development that is characteristic of central tolerance. This developmental blockade implies the presence of tolerizing autoantigens that are mimicked by the membrane-proximal external region of HIV-1 gp41. We identify human kynureninase (KYNU) and splicing factor 3b subunit 3 (SF3B3) as the primary conserved, vertebrate self-antigens recognized by the 2F5 and 4E10 antibodies, respectively. 2F5 binds the H4 domain of KYNU which contains the complete 2F5 linear epitope (ELDKWA). 4E10 recognizes an epitope of SF3B3 that is strongly dependent on hydrophobic interactions. Opossums carry a rare KYNU H4 domain that abolishes 2F5 binding, but they retain the SF3B3 4E10 epitope. Immunization of opossums with HIV-1 gp140 induced extraordinary titers of serum antibody to the 2F5 ELDKWA epitope but little or nothing to the 4E10 determinant. Identification of structural motifs shared by vertebrates and HIV-1 provides direct evidence that immunological tolerance can impair humoral responses to HIV-1.

scholarly journals Identification of Near-Pan-neutralizing Antibodies against HIV-1 by Deconvolution of Plasma Humoral Responses

Cell ◽  
2018 ◽  
Vol 173 (7) ◽  
pp. 1783-1795.e14 ◽  
Author(s):  
Mohammad Mohseni Sajadi ◽  
Amir Dashti ◽  
Zahra Rikhtegaran Tehrani ◽  
William D. Tolbert ◽  
Michael S. Seaman ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Humoral Responses ◽  
Hiv 1

scholarly journals Ablation of the Complementarity-Determining Region H3 Apex of the Anti-HIV-1 Broadly Neutralizing Antibody 2F5 Abrogates Neutralizing Capacity without Affecting Core Epitope Binding

2010 ◽  
Vol 84 (9) ◽  
pp. 4136-4147 ◽  
Author(s):  
Jean-Philippe Julien ◽  
Nerea Huarte ◽  
Rubén Maeso ◽  
Stefka G. Taneva ◽  
Annie Cunningham ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Titration Calorimetry ◽  
Peptide Epitope ◽  
Neutralizing Capacity ◽  
Epitope Binding ◽  
Hiv 1 ◽  
Complementarity Determining Region

ABSTRACT The identification and characterization of broadly neutralizing antibodies (bnAbs) against HIV-1 has formed a major research focus, with the ultimate goal to help in the design of an effective AIDS vaccine. One of these bnAbs, 2F5, has been extensively characterized, and residues at the apex of its unusually long complementarity-determining region (CDR) H3 loop have been shown to be crucial for neutralization. Structural studies, however, have revealed that the 100TLFGVPI100F apex residues of the CDR H3 loop do not interact directly with residues of its core gp41 epitope. In an attempt to gain better insight into the functional role of this element, we have recombinantly expressed native 2F5 Fab and two mutants in which either the apical Phe100B(H) residue was changed to an alanine or the CDR H3 residues 100TLFGVPI100F were replaced by a Ser-Gly dipeptide linker. Isothermal titration calorimetry (ITC) and competitive-binding enzyme-linked immunosorbent assays (ELISAs) rendered strikingly similar affinity constants (Kd [dissociation constant] of ∼20 nM) for linear peptide epitope binding by 2F5 Fabs, independent of the presence or absence of the apex residues. Ablation of the CDR H3 apex residues, however, abolished the cell-cell fusion inhibition and pseudovirus neutralization capacities of 2F5 Fab. We report competitive ELISA data that suggest a role of 2F5 CDR H3 apex residues in mediating weak hydrophobic interactions with residues located at the C terminus of the gp41 membrane proximal external region and/or membrane components in the context of core epitope binding. The present data therefore imply an extended 2F5 paratope that includes weak secondary interactions that are crucial for neutralization of Env-mediated fusion.

Induction of a Robust Humoral Response using HIV-1 VLPMPER-V3 as a Novel Candidate Vaccine in BALB/c Mice

2019 ◽  
Vol 17 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Fatemeh Tohidi ◽  
Seyed Mehdi Sadat ◽  
Azam Bolhassani ◽  
Ramin Yaghobi ◽  
Mona Sadat Larijani
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Candidate ◽  
Humoral Response ◽  
Cellular Responses ◽  
Immunodeficiency Virus ◽  
Potential Vaccine ◽  
Humoral Responses ◽  
Hiv 1

Background: Several approaches have not been successful to suppress HIV (Human immunodeficiency virus) infection among infected individuals or to prevent it yet. In order to expand strong HIV specific humoral and cellular responses, Virus-like particles (VLPs) as potential vaccines show significant increase in neutralizing antibodies secretion, T-cell count and also secretion of cytokines. Objective: This study aimed at immunological evaluation of VLPs harboring high copy of MPERV3 in BALB/c mice. Methods: Female BALB/c mice were immunized with homologous and heterologous primeboosting regimens of HIV-1 VLPMPER-V3. Their immune responses were evaluated for humoral responses (Total IgG and IgG isotyping) and cellular responses (IFN-γ, IL-5 secretion, in vitro CTL assay and T cell proliferation) and compared in immunized mice. Results: The data showed robust induction of humoral response in mice groups which received different regimens of VLP. Furthermore, analysis of cytokine profile indicated that the highest IL-5 secretion was related to VLP+M50 group and confirmed the dominance of Th2 immunity in this group. Conclusion: This study showed that VLP MPER-V3 as a potential vaccine candidate has the potency as an effective prophylactic vaccine and this finding guarantees further investigations to achieve a promising HIV-1 vaccine candidate.

scholarly journals Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001

2016 ◽  
Vol 90 (22) ◽  
pp. 10362-10378 ◽  
Author(s):  
Matthew R. Costa ◽  
Justin Pollara ◽  
Regina Whitney Edwards ◽  
Michael S. Seaman ◽  
Miroslaw K. Gorny ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Fc Receptor ◽  
Hiv Vaccine ◽  
Small Subset ◽  
Potential Contribution ◽  
Human Monoclonal Antibodies ◽  
Initial Report ◽  
Protein Boost ◽  
Hiv 1

ABSTRACTHIV-1 is able to elicit broadly potent neutralizing antibodies in a very small subset of individuals only after several years of infection, and therefore, vaccines that elicit these types of antibodies have been difficult to design. The RV144 trial showed that moderate protection is possible and that this protection may correlate with antibody-dependent cellular cytotoxicity (ADCC) activity. Our previous studies demonstrated that in an HIV vaccine phase I trial, the DP6-001 trial, a polyvalent Env DNA prime-protein boost formulation could elicit potent and broadly reactive, gp120-specific antibodies with positive neutralization activities. Here we report on the production and analysis of HIV-1 Env-specific human monoclonal antibodies (hMAbs) isolated from vaccinees in the DP6-001 trial. For this initial report, 13 hMAbs from four vaccinees in the DP6-001 trial showed broad binding to gp120 proteins of diverse subtypes both autologous and heterologous to vaccine immunogens. Equally cross-reactive Fc receptor-mediated functional activities, including ADCC and antibody-dependent cellular phagocytosis (ADCP) activities, were present with both immune sera and isolated MAbs, confirming the induction of nonneutralizing functional hMAbs by the DNA prime-protein boost vaccination. Elicitation of broadly reactive hMAbs by vaccination in healthy human volunteers confirms the value of the polyvalent formulation in this HIV vaccine design.IMPORTANCEThe roles of Fc receptor-mediated protective antibody responses are gaining more attention due to their potential contribution to the low-level protection against HIV-1 infection that they provided in the RV144 trial. At the same time, information about hMabs from other human HIV vaccine studies is very limited. In the current study, both immune sera and monoclonal antibodies from vaccinated humans showed not only high-level ADCC and ADCP activities but also cross-subtype ADCC and ADCP activities when a polyvalent DNA prime-protein boost vaccine formulation was used.

scholarly journals Antigenic and Immunogenic Study of Membrane-Proximal External Region-Grafted gp120 Antigens by a DNA Prime-Protein Boost Immunization Strategy

2007 ◽  
Vol 81 (8) ◽  
pp. 4272-4285 ◽  
Author(s):  
Mansun Law ◽  
Rosa M. F. Cardoso ◽  
Ian A. Wilson ◽  
Dennis R. Burton
Keyword(s):  
Neutralizing Antibodies ◽  
External Region ◽  
Membrane Proximal External Region ◽  
4E10 Epitope ◽  
Protein Boost ◽  
Immunodeficiency Virus ◽  
Monomeric Gp120 ◽  
Boost Immunization ◽  
Epitope Binding ◽  
Hiv 1

ABSTRACT The membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) gp41 is a target of broadly neutralizing monoclonal antibodies (MAbs) 2F5, 4E10, and Z13. Here we engrafted the MPER into the V1/2 region of HIV-1 gp120 to investigate the ability of the engineered antigens to elicit virus-neutralizing antibodies (NAbs). To promote the correct folding and presentation of the helical 4E10 epitope, we flanked the epitope with helical domains and manipulated the helix by sequential deletion of residues preceding the epitope. Binding of the recombinant proteins to MAb 4E10 increased four- to fivefold with the deletion of one or two residues, but it returned to the wild-type level when three residues were deleted, suggesting rotation of the 4E10 epitope along the helix. Immunization of mice and rabbits by electroporation-mediated DNA priming and protein boosting with these constructs elicited high levels of gp120-specific antibodies. A consistent NAb response against the neutralization-resistant, homologous JR-FL virus was detected in rabbits but not in mice. Analysis of the neutralizing activity revealed that the NAbs do not target the MPER or the V1, V2, or V3 region. Through this study, we learned the following. (i) The 4E10 epitope can be manipulated using a “rotate-the-helix” strategy that alters the helix register. However, presentation of this epitope in the immunogenic V1/2 region did not render it immunogenic in mice or rabbits. (ii) DNA vaccination with monomeric gp120-based antigens can elicit a consistent NAb response against the homologous neutralization-resistant virus by targeting epitopes outside the V1, V2, and V3 regions.

Neutralizing antibodies induced by liposomal HIV-1 glycoprotein 41 peptide simultaneously bind to both the 2F5 or 4E10 epitope and lipid epitopes

AIDS ◽  
2009 ◽  
Vol 23 (16) ◽  
pp. 2069-2077 ◽  
Author(s):  
Gary R Matyas ◽  
Lindsay Wieczorek ◽  
Zoltan Beck ◽  
Christina Ochsenbauer-Jambor ◽  
John C Kappes ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
4E10 Epitope ◽  
Hiv 1

scholarly journals Cross-neutralization of SARS-CoV-2 by HIV-1 specific broadly neutralizing antibodies and polyclonal plasma

2020 ◽  
Author(s):  
Nitesh Mishra ◽  
Sanjeev Kumar ◽  
Swarandeep Singh ◽  
Tanu Bansal ◽  
Nishkarsh Jain ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Cross Reactivity ◽  
Type I ◽  
Human Monoclonal Antibodies ◽  
Critical Feature ◽  
Cd4 Binding Site ◽  
Unique Nature ◽  
Hiv 1

AbstractCross-reactive epitopes (CREs) are similar epitopes on viruses that are recognized or neutralized by same antibodies. The S protein of SARS-CoV-2, similar to type I fusion proteins of viruses such as HIV-1 envelope (Env) and influenza hemagglutinin, is heavily glycosylated. Viral Env glycans, though host derived, are distinctly processed and thereby recognized or accommodated during antibody responses. In recent years, highly potent and/or broadly neutralizing human monoclonal antibodies (bnAbs) that are generated in chronic HIV-1 infections have been defined. These bnAbs exhibit atypical features such as extensive somatic hypermutations, long complementary determining region (CDR) lengths, tyrosine sulfation and presence of insertions/deletions, enabling them to effectively neutralize diverse HIV-1 viruses despite extensive variations within the core epitopes they recognize. As some of the HIV-1 bnAbs have evolved to recognize the dense viral glycans and cross-reactive epitopes (CREs), we assessed if these bnAbs cross-react with SARS-CoV-2. Several HIV-1 bnAbs showed cross-reactivity with SARS-CoV-2 while one HIV-1 CD4 binding site bnAb, N6, neutralized SARS-CoV-2. Furthermore, neutralizing plasma antibodies of chronically HIV-1 infected children showed cross neutralizing activity against SARS-CoV-2. Collectively, our observations suggest that human monoclonal antibodies tolerating extensive epitope variability can be leveraged to neutralize pathogens with related antigenic profile.ImportanceIn the current ongoing COVID-19 pandemic, neutralizing antibodies have been shown to be a critical feature of recovered patients. HIV-1 bnAbs recognize extensively diverse cross-reactive epitopes and tolerate diversity within their core epitope. Given the unique nature of HIV-1 bnAbs and their ability to recognize and/or accommodate viral glycans, we reasoned that the glycan shield of SARS-CoV-2 spike protein can be targeted by HIV-1 specific bnAbs. Herein, we showed that HIV-1 specific antibodies cross-react and neutralize SARS-CoV-2. Understanding cross-reactive neutralization epitopes of antibodies generated in divergent viral infections will provide key evidence for engineering so called super-antibodies (antibodies that can potently neutralize diverse pathogens with similar antigenic features). Such cross-reactive antibodies can provide a blueprint upon which synthetic variants can be generated in the face of future pandemics.

scholarly journals Breaching peripheral tolerance promotes the production of HIV-1–neutralizing antibodies

2017 ◽  
Vol 214 (8) ◽  
pp. 2283-2302 ◽  
Author(s):  
Kristin M.S. Schroeder ◽  
Amanda Agazio ◽  
Pamela J. Strauch ◽  
Sean T. Jones ◽  
Scott B. Thompson ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Serum Levels ◽  
Immunological Tolerance ◽  
Peripheral Tolerance ◽  
Tier 2 ◽  
Histone H2a ◽  
Autoantibody Response ◽  
Alum Treatment ◽  
Hiv 1

A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env. Importantly, experimentally breaching immunological tolerance in wild-type mice also leads to the production of tier 2 HIV-1–neutralizing antibodies, which increase in breadth and potency following Env immunization. In both genetically prone and experimentally induced mouse models of autoimmunity, increased serum levels of IgM anti-histone H2A autoantibodies significantly correlated with tier 2 HIV-1 neutralization, and anti-H2A antibody clones were found to neutralize HIV-1. These data demonstrate that breaching peripheral tolerance permits a cross-reactive HIV-1 autoantibody response able to neutralize HIV-1.

scholarly journals Sensitivity to Broadly Neutralizing Antibodies of Recently Transmitted HIV-1 Clade CRF02_AG Viruses with a Focus on Evolution over Time

2018 ◽  
Vol 93 (2) ◽  
Author(s):  
Karl Stefic ◽  
Mélanie Bouvin-Pley ◽  
Asma Essat ◽  
Clara Visdeloup ◽  
Alain Moreau ◽  
...  
Keyword(s):  
Clinical Trials ◽  
West Africa ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Broadly Neutralizing Antibodies ◽  
Human Monoclonal Antibodies ◽  
Large Panel ◽  
Cd4 Binding Site ◽  
Major Progress ◽  
Hiv 1

ABSTRACT Broadly neutralizing antibodies (bnAbs) are promising agents for prevention and/or treatment of HIV-1 infection. However, the diversity among HIV-1 envelope (Env) glycoproteins impacts bnAb potency and breadth. Neutralization data on the CRF02_AG clade are scarce although it is highly prevalent in West Africa and Europe. We assessed the sensitivity to bnAbs of a panel of 33 early transmitted CRF02_AG viruses over a 15-year period of the French epidemic (1997 to 2012). Env pseudotyped CRF02_AG viruses were best neutralized by the CD4 binding site (CD4bs)-directed bnAbs (VRC01, 3BNC117, NIH45-46G54W, and N6) and the gp41 membrane-proximal external region (MPER)-directed bnAb 10E8 in terms of both potency and breadth. We observed a higher resistance to bnAbs targeting the V1V2-glycan region (PG9 and PGT145) and the V3-glycan region (PGT121 and 10-1074). Combinations were required to achieve full coverage across this subtype. We observed increased resistance to bnAbs targeting the CD4bs linked to the diversification of CRF02_AG Env over the course of the epidemic, a phenomenon which was previously described for subtypes B and C. These data on the sensitivity to bnAbs of CRF02_AG viruses, including only recently transmitted viruses, will inform future passive immunization studies. Considering the drift of the HIV-1 species toward higher resistance to neutralizing antibodies, it appears necessary to keep updating existing panels for evaluation of future vaccine and passive immunization studies. IMPORTANCE Major progress occurred during the last decade leading to the isolation of human monoclonal antibodies, termed broadly neutralizing antibodies (bnAbs) due to their capacity to neutralize various strains of HIV-1. Several clinical trials are under way in order to evaluate their efficacy in preventive or therapeutic strategies. However, no single bnAb is active against 100% of strains. It is important to gather data on the sensitivity to neutralizing antibodies of all genotypes, especially those more widespread in regions where the prevalence of HIV-1 infection is high. Here, we assembled a large panel of clade CRF02_AG viruses, the most frequent genotype circulating in West Africa and the second most frequent found in several European countries. We evaluated their sensitivities to bnAbs, including those most advanced in clinical trials, and looked for the best combinations. In addition, we observed a trend toward increased resistance to bnAbs over the course of the epidemic.

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