Study On Precisely Designed MPER Based Conformational Peptide Induced 10E8-like Antibody Against HIV-1

Recent studies have demonstrated that the membrane-proximal external region(MPER)of Human Immunodeficiency Virus 1(HIV-1)glycoprotein 41 contains a series of epitopes for human monoclonal antibodies,including 2F5,Z13e1,4E10,and 10E8,which were isolated from HIV-1-infected individuals and exhibited broad neutralizing activities.This suggests that MPER is a good target for the development of effective HIV-1 vaccines.However,many studies have suggested that it is difficult to induce antibodies with similar broad neutralizing activities using MPER-based peptide antigens,due to poor immunogenicity,the need for stapled confirmation and membrane context.10E8 antibody shows the most potency among all the broadly neutralizing antibodies.Based on the crystal structure information of 10E8,we first performed a series of chemical modifications on MPER-derived 10E8-specific epitope,including substitution with an(S)-?-(2?-pentenyl)alanine containing an olefin-bearing tether and ruthenium-catalyzed olefin metathesis to generate a more stable immunogen.The immunogenic peptide(designated as T10HE)contained the MPER-derived 10E8-specific epitope fused to T-helper-cell epitopes from Tetanus Toxin(TT)through a flexible polyethylene glycol linker(PEG2).The peptide showed a significantly stabilized ?-helix structure and the chemical modifications did not affect its capacity to bind the 10E8 antibody,as evaluated with an enzyme linked immunosorbent assay(ELISA)and surface plasmon resonance binding assay(SPR assay).We then evaluated the efficacies of the T10 HE epitope vaccines with a standard vaccination procedure,in which mice were primed with T10 HE immunogen and boosted with HIV-1 JRFL pseudoviruses.Compared with other designs of immunization strategy,T10 HE induced higher titers of 10E8-like antibodies and more importantly,the induced antibodies have enhanced antiviral potency against HIV-1 strains of both X4 and R5 tropism and exhibited greater degree of broad neutralizing activity.In conclusion,we reported that 10E8-like neutralizing antibodies with effective anti-HIV-1 activity can be readily induced using a precisely designed and more stable immunogenic peptide containing the 10E8-specific epitope.This study provides a novel way to induce efficient HIV-1 antibodies with broad neutralizing activities.