The CD4 Binding Site on HIV gp120 as a Vaccine Antigen

Montana State University (Bozeman), Bozeman MT

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Abstract

DESCRIPTION: (Provided by Applicant) Design of an effective vaccine against HIV must take into account the high degree of variability in the sequence of the envelope proteins that has been observed in clinical isolates, and the high mutation rate of the virus. The envelope glycoprotein gp120 and its precursor gp160 have been ineffective against clinical isolates of HIV when used as vaccine candidates. HIV-neutralizing antibodies are elicited primarily against the third variable (V3) loop of the sequence. Late in HIV infection, however, neutralizing antibodies with broader strain specificity are produced which appear to be directed at the three-dimensional shape of the CD4 binding site. Our hypothesis is that this part of gp120 will make a more effective vaccine antigen than the whole protein. We therefore want to construct recombinant or synthetic molecules that display this conformation-dependent structure. Our immediate goals are to: 1) find peptide structures that can mimic the sites that the neutralizing antibodies bind to; 2) display these peptides on the capsid protein of a plant virus that can be expressed and assembled in yeast, and determine which constructs can bind anti-HIV antibodies; 3) synthesize the peptide sequences and determine their three-dimensional structures when bound to the antibodies; 4) immunize mice and rabbits with the recombinant plant virus protein or synthetic peptide-protein conjugates and determine whether HIV-neutralizing antibodies are produced. The information obtained from X-ray crystallography of the recombinant viruses and peptide-antibody complexes will be used to design better antigens that can elicit a more effective immune response to the virus.