title: Generation of HIV-1 potent and broad neutralizing antibodies by immunization with postfusion HR1/HR2 complex.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculté de Medicine de Saint Etienne, Université de Lyon, Lyon, France.
authors.forename: Reham
authors.initials: R
authors.lastname: Dawood
authors.forename: Fahd
authors.initials: F
authors.lastname: Benjelloun
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Pin
authors.forename: Amadou
authors.initials: A
authors.lastname: Kone
authors.forename: Blandine
authors.initials: B
authors.lastname: Chanut
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jospin
authors.forename: Frederic
authors.initials: F
authors.lastname: Lucht
authors.forename: Bernard
authors.initials: B
authors.lastname: Verrier
authors.forename: Christaine
authors.initials: C
authors.lastname: Moog
authors.forename: Christain
authors.initials: C
authors.lastname: Genin
authors.forename: Stéphane
authors.initials: S
authors.lastname: Paul
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000097:blood*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007114:Immunization; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D017433:Protein Structure, Secondary; D012091:Repetitive Sequences, Nucleic Acid; D014162:Transfection; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D008562:Membrane Glycoproteins; D014759:Viral Envelope Proteins