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.