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 (MPR _649-684) is an attractive vaccine target for humoral immunity that blocks viral transcytosis across the mucosal epithelia. However, induction of high-titer MPR _649-684-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 MPR _649-684 (F1-V-MPR _649-684). We employed systemic immunization for initial feasibility analyses. Despite strong immunogenicity demonstrated for the immunogen, repeated systemic immunizations of mice with F1-V-MPR _649-684 hardly induced MPR _649-684-specific IgG. In contrast, a single immunization with F1-V-MPR _649-684 mounted a significant anti-MPR _649-684 IgG response in animals that were primed with another MPR _649-684 fusion protein based on the cholera toxin B subunit. Additional boost immunizations with F1-V-MPR _649-684 recalled and maintained the antibody response and expanded the number of specific antibody-secreting B cells. Thus, while F1-V-MPR _649-684 alone was not sufficiently immunogenic to induce detectable levels of MPR _649-684-specific antibodies, these results suggest that prime-boost immunization using heterologous antigen-display platforms may overcome the poor humoral immunogenicity of MPR _649-684 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.