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177 Peptide Linkers Between Natural Antibodies and HIV Target

Perdomo, Maria; Sällberg, Matti; Vahlne, Anders

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 74
doi: 10.1097/01.qai.0000397360.91663.81

Division of Clinical Microbiology, Karolinska Institutet, Stockholm Sweden

In human serum approximately 1 to 8% of the total IgM and 1 to 2,4% of the total IgG recognize the epitope gal(a1,3)gal, which is part of a penta-saccharide present mainly on endothelial cells of all mammals except humans and old world monkeys. These natural antibodies have been shown to participate in the antibody-mediated opsonization of particles and in the induction of the classical cascade of the complement. Moreover, these antibodies can trigger the activation of NK cells via CD16 recognition of the Fc fraction of the antibody and induce an antibody-dependent cellular cytotoxicity (ADCC). We thought it would be useful to temporarily be able to redirect this high level preexisting antibody pool to a new antigen, which rapidly would increase the pool of biologically active antibodies with a pre-determined specificity as an alternative to administering a monoclonal antibody. To explore this possibility we chose to target the receptor-binding region of the envelope protein (gp120) of the human immunodeficiency virus (HIV). The interaction between gp120 and its receptor the CD4 molecule is highly conserved and involves only a limited amount of residues. The envelope glycoprotein binds to 22 residues on the D1 region of the CD4 receptor located between amino acids 25 to 64 and the atomic interactions are well characterized. As previously published, we could show that CD4-derived, gp120-binding, synthetic peptides chemically linked to gal(α1,3)gal can redirect these natural antibodies and improve the HIV-1-neutralizing activity of the CD4-derived peptides in vitro and conferred antibody dependent cellular cytotoxicity after the addition of normal human sera. We have now extended these studies using a sterical mimetic of CD4 withou sequence hology and peptides derived from CCR5. I will also discuss how we now are employing a random RNA library to select peptides binding to new targets.

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