anti-alphaGal_HIV - Neutralization of HIV-1 by redirection...

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Neutralization of HIV-1 by redirection of natural antibodies Maria F. Perdomo*, Michael Levi , Matti Sa ¨llberg*, and Anders Vahlne* *Division of Clinical Microbiology, Karolinska Institutet, Karolinska University Hospital at Huddinge F-68, SE-141 86 Stockholm, Sweden; and Tripep AB, Ha ¨lsova ¨gen 7, SE-141 57 Huddinge, Sweden Communicated by Robert C. Gallo, University of Maryland, Baltimore, MD, June 15, 2008 (received for review February 15, 2008) The great variability and high glycosylation of gp120 poses a great challenge for the design of a functional immune therapy. The binding region of the CD4 receptor to gp120, however, is well conserved and may constitute a target to limit viral entry and infectivity. Our strategy consists in using a preexisting pool of natural antibodies directed toward the gal( 1,3)gal disaccharide and to redirect it to HIV. We here show that using CD4-derived, gp120-binding, synthetic peptides chemically linked to gal( 1,3)gal can redirect these natural antibodies and improve the HIV-1 neutralizing activity of the CD4-derived pep- tides in vitro . Importantly, the binding of the CD4-gal( 1,3)gal pep- tides to HIV-1–infected cells conferred antibody-dependent cellular cytotoxicity after the addition of human sera. Thus, the temporary redirection of naturally occurring antibodies and their biological activities to a new antigen represents a completely new way of targeting a human disease. ADCC peptides gal( 1,3)gal CD4 N atural antibodies play an important role in the first line of defense against many viral and bacterial infections, providing a link between the innate and adaptive immune response (1). They have been shown to be important in the antibody-mediated opso- nization of particles by macrophages and in the induction of the classic cascade of the complement (2). Moreover, these antibodies can trigger the activation of natural killer (NK) cells via CD16 recognition of the Fc fraction of the antibody and induce an antibody-dependent cellular cytotoxicity (ADCC) (3). In human serum, 1–8% of the total IgM and 1 to 2.4% of the total IgG recognize the epitope gal( 1,3)gal (4), which is part of a pentasac- charide present mainly on endothelial cells of all mammals except humans and old world monkeys (4–6). Thus, it would be very useful to temporarily be able to redirect this high-level preexisting anti- body pool to a new antigen, which rapidly would increase the pool of biologically active antibodies with a predetermined 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 HIV. The interaction between gp120 and its receptor, the CD4 molecule, is highly conserved and involves only a limited amount of residues.
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