title: Humoral immunogenicity of an HIV-1 envelope residue 649-684 membrane-proximal region peptide fused to the plague antigen F1-V.
abstract: 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.
authors.affiliation: Center for Infectious Diseases and Vaccinology at the Biodesign Institute and School of Life Sciences, P.O. Box 874501, Arizona State University, Tempe, AZ 85287-4501, USA. n.matoba@louisville.edu
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Matoba
authors.forename: Namrata Rahul
authors.initials: NR
authors.lastname: Shah
authors.forename: Tsafrir S
authors.initials: TS
authors.lastname: Mor
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology; D002772:Cholera Toxin / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D056724:Immunity, Humoral; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010446:Peptide Fragments / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology*; D014611:Vaccination; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; C545841:HIV-1 envelope protein gp41 (649-684); D007074:Immunoglobulin G; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014765:Viral Vaccines; C086725:caf1 protein, Yersinia pestis; D002772:Cholera Toxin