Synthetic cyclic peptides as a compound of an HIV-1 vaccine.
AIDS remains a major health issue worldwide. 30 millions peoples have died from the disease caused by the HIV-1 virus. In the search for an HIV-1 vaccine we must identify specific regions in the HIV-1 envelop proteins, gp120 and gp41, that are critical for viral entry into its target cells and generate an effective neutralizing antibody response against these regions. One such epitope is the V3 region which forms the binding site binds to the chemokine co-receptors and is an important target for neutralizing antibodies. We have identified a conserved ?-hairpin structure for the V3 loop and developed strategies to stabilized linear V3 peptides to the desirable ?-hairpin conformation using disulfide bond. The outlined technology relates to the design and application of constrained V3 peptides to elicit a broadly neutralizing HIV-1 antibody response.
Constrained V3 peptides can be used as a component of an anti-HIV-1 vaccine to elicit HIV-1 neutralizing antibody response in healthy individuals.
447-52D derived from an HIV-1 infected donor is one of the most potent and most broadly neutralizing human monoclonal antibodies, and in a study of HIV-1 broadly neutralizing antibodies 447-52D neutralized 45% of the clade-B isolates tested and was capable of neutralizing both X4 and R5 viruses as well as some primary isolates. We designed peptide immunogen to mimic the 447-52D bound conformation and use these peptides to elicit a neutralizing antibody response
Synthetic peptides offer an attractive option for the development of a V3-directed vaccine. However, immunization with flexible linear peptides may result in an immune response to multiple conformations, many of which differ from the native conformation of the corresponding region in the cognate protein. We have shown that optimization of the location of a disulfide bond in peptides constrained to mimic the ?-hairpin conformation of the V3, yields an immunogen that elicits significantly stronger HIV-1 neutralizing response in rabbits in comparison with the homologous linear V3 peptide. The immune sera were able to neutralize a panel of neutralization sensitive clade-B strains including both X4 and R5 viruses. Neutralization of an HIV-1 strain that differ from the immunizing peptide by four mutations, a two residue insertion and a deletion was demonstrated. The most effective immunogen was also able to neutralize primary isolates that are more resistant to neutralization such as SS1196 and 6535.