Humoral immunogenicity of an HIV-1 envelope residue 649–684 membrane-proximal region peptide fused to the plague antigen F1-V

The membrane-proximal region spanning residues 649–684 of the HIV-1 envelope protein gp41 (MPR649–684) is an attractive vaccine target for humoral immunity that blocks viral transcytosis across the mucosal epithelia. However, induction of high-titer MPR649–684-specific antibodies remains a challenging task. To explore potential solutions for this challenge, we tested a new translational fusion protein comprising the plague F1-V antigen and MPR649–684 (F1-V–MPR649–684). We employed systemic immunization for initial feasibility analyses. Despite strong immunogenicity demonstrated for the immunogen, repeated systemic immunizations of mice with F1-V–MPR649–684 hardly induced MPR649–684-specific IgG. In contrast, a single immunization with F1-V–MPR649–684 mounted a significant anti-MPR649–684 IgG response in animals that were primed with another MPR649–684 fusion protein based on the cholera toxin B subunit. Additional boost immunizations with F1-V–MPR649–684 recalled and maintained the antibody response and expanded the number of specific antibody-secreting B cells. Thus, while F1-V–MPR649–684 alone was not sufficiently immunogenic to induce detectable levels of MPR649–684-specific antibodies, these results suggest that prime-boost immunization using heterologous antigen-display platforms may overcome the poor humoral immunogenicity of MPR649–684 for the induction of durable humoral immunity. Further studies are warranted to evaluate the feasibility of this strategy in mucosal immunization. Lastly, our findings add to a growing body of evidence in support of this strategy for immunogen design for poorly immunogenic epitopes besides the MPR of HIV-1's transmembrane envelope protein.