The principal neutralization determinant of HIV-1 elicits broadly neutralizing antibodies.
Int Conf AIDS 1991 Jun 16-21; 7:88 (abstract no. F.A.3) Herlihy WC, Javaherian K, LaRosa GJ, Bolognesi DP, Matthews TJ, Putney SD; Repligen Corporation, One Kendall Square, Cambridge, MA, USA
The principal binding site for HIV-1 neutralizing antibodies (the principal neutralization determinant or PND) is within a disulfide loop in the third variable domain of the external envelope protein, gp120. The amino acid sequence of the PND is variable and PND-containing peptides generally elicit isolate-restricted neutralizing antibody. Because of this it has been thought that vaccine development focusing on the PND may be difficult. However, analysis of the sequence of the PND of 245 virus isolates shows that conserved PND sequences are present in a majority of HIV-1 isolates (Science (1990) 249: 932). In addition, the structural motif beta-strand--type II beta-turn--beta-strand--alpha-helix is predicted to be Conserved. One of these conserved sequences is Gly-Pro-Gly-Arg-Ala-Phe (GPGRAF) that is present in the PND in 60% of HIV-1 isolates. We have found that antisera elicited by and binding to GPGRAF containing peptides neutralize all four isolates assayed that contain GPGRAF in the PND (including the divergent isolates IIIB and MN) but not three isolates lacking that hexapeptide. Peptide competition experiments show that the neutralizing antibodies are completely absorbed by a peptide containing only the GPGRAF sequence. Thus a single synthetic peptide induces antibodies that neutralize divergent HIV isolates by binding to conserved PND sequences. Because the PND contains several such conserved sequences and secondary structures that can serve as targets for antibody neutralization, this data suggests that a peptide based vaccine can be developed that can protect against infection by a majority of HIV-1 isolates.
Keywords: AEGIS, HIV-1, HIV Antibodies, Peptides, Immune Sera, Binding Sites, Disulfides, ICA7 910616
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