Generation of HIV-1 potent and broad neutralizing antibodies by immunization with postfusion HR1/HR2 complex

Dawood, Rehama; Benjelloun, Fahda; Pin, Jean J.b; Kone, Amadoua; Chanut, Blandinea; Jospin, Fabiennea; Lucht, Frederica; Verrier, Bernardc; Moog, Christained; Genin, Christaina; Paul, Stéphanea

doi: 10.1097/QAD.0b013e32835cfca5
Basic Science

Background: The envelope glycoproteins are major targets for HIV vaccines. The N-terminal and the C-terminal regions of the gp41 interact to form six helix bundles that are responsible for the fusion between the viral and the target cell membranes. Monoclonal antibodies (Abs) able to disrupt the formation of this complex or to interfere with it could inhibit HIV fusion. Most of the well described gp41-specific broadly neutralizing Abs target conformational epitopes within the membrane proximal region of gp41 (MPER) and recognize linear peptides.

Method and results: In this study, a stable human transfected cell line, expressing a well folded heptad repeat regions 1 (HR1)/HR2 postfusion complex was developed. Transfected cells were highly immunogenic in mice and allowed the generation of 40 complex specific B-cell clones. Three of them were able to neutralize efficiently both HIV-1 laboratory adapted virus and primary isolates from different clades. Two neutralizing Abs (Nabs) FC-2 and FC-3 bound to a recombinant folded gp140 and blocked with a high potency HR1/HR2 fusion complex formation in vitro. The conformational epitopes of the three antibodies are different to 2F5, 4E10, D5 or NC-1 and mainly located in the MPER region. Abs were capable of inhibiting syncytium formation by blocking spatial interactions between HR1 and HR2 regions.

Conclusion: These findings suggest that immunogenicity of gp41 is achievable and that the use of a fusion complex expressing human cell line is a highly potent immunogen to generate neutralizing antibodies against gp41 envelope glycoprotein.

aGIMAP EA3064, Faculté de Medicine de Saint Etienne, Université de Lyon

bDENDRITICS SAS, Bioparc Laennec

cInstitut de Biologie et Chimie des Protéines, FRE 3310 CNRS/UCBL, Lyon

dINSERM-U748, Institute of Virology, Strasbourg, France.

Correspondence to Dr Stéphane Paul, Faculté de Medicine de Saint Etienne, Université de Lyon, Lyon, France. E-mail: stephane.paul@chu-st-etienne.fr

Received 20 July, 2012

Revised 12 November, 2012

Accepted 23 November, 2012

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© 2013 Lippincott Williams & Wilkins, Inc.