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      Proteins mimicking epitope of HIV-1 virus neutralizing antibody induce virus-neutralizing sera in mice

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          Abstract

          Background

          The development of an effective vaccine preventing HIV-1 infection is hindered by the enormous antigenic variability and unique biochemical and immunological properties of HIV-1 Env glycoprotein, the most promising target for HIV-1 neutralizing antibody. Functional studies of rare elite neutralizers led to the discovery of broadly neutralizing antibodies.

          Methods

          We employed a highly complex combinatorial protein library derived from a 5 kDa albumin-binding domain scaffold, fused with support protein of total 38 kDa, to screen for binders of broadly neutralizing antibody VRC01 paratope. The most specific binders were used for immunization of experimental mice to elicit Env-specific antibodies and to test their neutralization activity using a panel of HIV-1 clade C and B pseudoviruses.

          Findings

          Three most specific binders designated as VRA017, VRA019, and VRA177 exhibited high specificity to VRC01 antibody. Immunized mice produced Env-binding antibodies which neutralize eight of twelve HIV-1 Tier 2 pseudoviruses. Molecular modelling revealed a shape complementarity between VRA proteins and a part of VRC01 gp120 interacting surface.

          Interpretation

          This strategy based on the identification of protein replicas of broadly neutralizing antibody paratope represents a novel approach in HIV-1 vaccine development. This approach is not affected by low immunogenicity of neutralization-sensitive epitopes, variability, and unique biochemical properties of HIV-1 Env used as a crucial antigen in the majority of contemporary tested vaccines.

          Fund

          Czech Health Research Council 15-32198A, Ministry of Health, Czech Republic.

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          Most cited references41

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          How good is automated protein docking?

          Dmitri Beglov, Tanggis Bohnuud, Scott Mottarella … (2013)
          The protein docking server ClusPro has been participating in critical assessment of prediction of interactions (CAPRI) since its introduction in 2004. This article evaluates the performance of ClusPro 2.0 for targets 46-58 in Rounds 22-27 of CAPRI. The analysis leads to a number of important observations. First, ClusPro reliably yields acceptable or medium accuracy models for targets of moderate difficulty that have also been successfully predicted by other groups, and fails only for targets that have few acceptable models submitted. Second, the quality of automated docking by ClusPro is very close to that of the best human predictor groups, including our own submissions. This is very important, because servers have to submit results within 48 h and the predictions should be reproducible, whereas human predictors have several weeks and can use any type of information. Third, while we refined the ClusPro results for manual submission by running computationally costly Monte Carlo minimization simulations, we observed significant improvement in accuracy only for two of the six complexes correctly predicted by ClusPro. Fourth, new developments, not seen in previous rounds of CAPRI, are that the top ranked model provided by ClusPro was acceptable or better quality for all these six targets, and that the top ranked model was also the highest quality for five of the six, confirming that ranking models based on cluster size can reliably identify the best near-native conformations. Copyright © 2013 Wiley Periodicals, Inc.
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            PIPER: an FFT-based protein docking program with pairwise potentials.

            Dima Kozakov, Ryan Brenke, Stephen R Comeau … (2006)
            The Fast Fourier Transform (FFT) correlation approach to protein-protein docking can evaluate the energies of billions of docked conformations on a grid if the energy is described in the form of a correlation function. Here, this restriction is removed, and the approach is efficiently used with pairwise interaction potentials that substantially improve the docking results. The basic idea is approximating the interaction matrix by its eigenvectors corresponding to the few dominant eigenvalues, resulting in an energy expression written as the sum of a few correlation functions, and solving the problem by repeated FFT calculations. In addition to describing how the method is implemented, we present a novel class of structure-based pairwise intermolecular potentials. The DARS (Decoys As the Reference State) potentials are extracted from structures of protein-protein complexes and use large sets of docked conformations as decoys to derive atom pair distributions in the reference state. The current version of the DARS potential works well for enzyme-inhibitor complexes. With the new FFT-based program, DARS provides much better docking results than the earlier approaches, in many cases generating 50% more near-native docked conformations. Although the potential is far from optimal for antibody-antigen pairs, the results are still slightly better than those given by an earlier FFT method. The docking program PIPER is freely available for noncommercial applications. (c) 2006 Wiley-Liss, Inc.
            Article 0 comments Cited 211 times – based on 0 reviews     Review now
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              Recent progress in broadly neutralizing antibodies to HIV

              Devin Sok, Dennis R. Burton (2018)
              In this Review, we highlight some recent developments in the discovery and application of broadly neutralizing antibodies (bnAbs) to human immunodeficiency virus (HIV); i.e., antibodies able to neutralize diverse isolates of HIV. We consider the characterization of novel bnAbs, recent data on the effects of bnAbs in vivo in humans and animal models, and the importance of both kinds of data for the application of Abs to prophylaxis and therapy and to guide vaccine design. We seek to place newly discovered bnAbs in the context of existing bnAbs, and we explore the various characteristics of the antibodies that are most desirable for different applications.
              Article 0 comments Cited 191 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jaroslav Turanek
                Petr Maly
                Milan Raska
                Journal
                Journal ID (nlm-ta): EBioMedicine
                Journal ID (iso-abbrev): EBioMedicine
                Title: EBioMedicine
                Publisher: Elsevier
                ISSN (Electronic): 2352-3964
                Publication date PMC-release: 20 September 2019
                Publication date Collection: September 2019
                Publication date (Electronic): 20 September 2019
                Volume: 47
                Pages: 247-256
                Affiliations
                [a ]Department of Immunology, Palacky University in Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic
                [b ]Laboratory of Ligand Engineering, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
                [c ]Laboratory of Structural Bioinformatics of Proteins, Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Prumyslova 595, Vestec 252 50, Czech Republic
                [d ]Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Hudcova 70, Brno 621 00, Czech Republic
                Author notes
                [** ]Correspondence to: Palacky University in Olomouc, Hnevotinska 3, Olomouc 779 00, Czech Republic. milan.raska@ 123456upol.cz
                [1]

                These authors contributed equally to this work

                Article
                Publisher ID: S2352-3964(19)30450-5
                DOI: 10.1016/j.ebiom.2019.07.015
                PMC ID: 6796546
                PubMed ID: 31544770
                SO-VID: e5f594bc-810a-45f8-b38b-a17c602eb7a6
                Copyright © © 2019 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 17 April 2019
                Date revision received : 28 June 2019
                Date accepted : 4 July 2019
                Categories
                Subject: Research paper

                Keywords: neutralizing antibody,albumin-binding domain scaffold,combinatorial protein library,antibody paratope mimetics,protein docking,hiv-1 vaccine
                Data availability:
                Keywords: neutralizing antibody, albumin-binding domain scaffold, combinatorial protein library, antibody paratope mimetics, protein docking, hiv-1 vaccine

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