The caveolin-1 binding domain of HIV-1 glycoprotein gp41 (CBD1) contains several overlapping neutralizing epitopes.
The CBD1 peptide (SLEQIWNNMTWMQWDK), corresponding to the consensus caveolin-1 binding domain in HIV-1 envelope glycoprotein gp41 (CBD1), elicits the production of antibodies that inhibit infection of primary CD4(+) T lymphocytes by various primary HIV-1 isolates. Here we show that HIV-neutralizing antibodies against CBD1 react with multiple conformational epitopes that overlap the highly conserved caveolin-1 binding motif (CBM) with the N-terminal conserved isoleucine residue. The CBM-based peptides IWNNMTWMQW and IWNNMTW when fused to a T helper epitope are immunogenic by inducing high titer CBM-specific antibodies capable of neutralizing HIV-1 infection in primary T lymphocyte cultures. Interestingly, neutralizing immune sera raised against a given peptide do not cross-react with related CBM-derived peptides, thus suggesting the existence of distinct neutralizing epitopes that probably reflect the dynamic conformational features of CBD1. In accord with this, the mixture of neutralizing immune sera raised against several CBM-derived peptides exerts a synergistic neutralizing activity against HIV-1 infection. Finally, the existence of several distinct overlapping epitopes in CBD1 is confirmed by murine monoclonal antibodies that we generated against the CBM-derived chimeric peptides. Our results indicate that CBD1- and CBM-based peptides mimic distinct dynamic conformations of CBD1, and thus such peptides could provide specific immunogens for an efficient vaccine preparation against HIV/AIDS infection.
Benferhat
Rima
R
UPR 2228 CNRS, Université Paris Descartes, 45 rue des Saints Pères, 75270 Paris Cedex 06, France.
Krust
Bernard
B
Rey-Cuillé
Marie-Anne
MA
Hovanessian
Ara G
AG
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001665:Binding Sites; D051242:Caveolin 1 / Q000378:metabolism*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte; D006168:Guinea Pigs; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007114:Immunization; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011817:Rabbits
D000911:Antibodies, Monoclonal; D051242:Caveolin 1; D018984:Epitopes, T-Lymphocyte; D015700:HIV Envelope Protein gp41; C514787:gp41 protein, Human immunodeficiency virus 1