Reverse Immunology Approach to Define a New HIV-gp41-Neutralizing Epitope.

Karim Dorgham,Patrice Debré,Vincent Vieillard,Christophe Piesse,Olivier Lucar,Cedric Pionneau,Delphine Sterlin,Pablo Guardado-Calvo,Philippe Karoyan,Guy Gorochov,Solenne Chardonnet,Tahar Bouceba,Nicolas Pietrancosta,Amel Affoune

doi:10.1155/2019/9804584

Abstract

The design of immunogens susceptible to elicit potent and broadly neutralizing antibodies against the human immunodeficiency virus type 1 (HIV-1) remains a veritable challenge in the course of vaccine development. Viral envelope proteins adopt different conformational states during the entry process, allowing the presentation of transient neutralizing epitopes. We focused on the highly conserved 3S motif of gp41, which is exposed to the surface envelope in its trimeric prefusion state. Vaccination with a W614A-modified 3S peptide induces in animals neutralizing anti-HIV-1 antibodies among which we selected clone F8. We used F8 as bait to select for W614A-3S phage-peptide mimics. Binding and molecular docking studies revealed that F8 interacts similarly with W614A-3S and a Mim_F8-1 mimotope, despite their lack of sequence homology, suggesting structural mimicry. Finally, vaccination of mice with the purified Mim_F8-1 phage elicited HIV-1-neutralizing antibodies that bound to the cognate W614A-3S motif. Collectively, our findings provide new insights into the molecular design of immunogens to elicit antibodies with neutralizing properties.

Highlights

Despite the success of antiretroviral therapy, which has turned human immunodeficiency virus type 1 (HIV-1) infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed
All Monoclonal antibodies (mAbs) were of the IgG1 isotype, and the sequence analysis of their variable domains revealed that the F8 and C9 clones secreted the same mAb, whereas B8 and G9 clones secreted identical mAbs, leading to the identification of three different mAbs (B8, F8, and G6; Supplemental Table I)
The variable domains of the heavy chains of the three mAbs were very different in terms of the V/D/J gene family used in the junction and regarding the amino acid sequences of the CDR1, 2, and 3 (Supplemental Table I)

Summary

Introduction

Despite the success of antiretroviral therapy, which has turned human immunodeficiency virus type 1 (HIV-1) infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. Other mechanisms of immune evasion by HIV-1 are mediated by the nature of the native envelope (Env) spikes on the viral surface that mediate infection through receptor binding and fusion and that are the major targets for virus-neutralizing antibodies (Abs) [1]. Neutralizing mAb a native closed form, shifting toward more open conformations. In agreement with this model, while breathing, some neutralizing epitopes that are not accessible in the native state become available in the relaxed conformation (e.g., the CD4 binding site epitope recognized by the IgG1b12), whereas other broadly neutralizing Abs, such as VRC01, lock down the spike in its native closed conformation suppressing further breathing [2]

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Conclusion