title: Modulating immunogenic properties of HIV-1 gp41 membrane-proximal external region by destabilizing six-helix bundle structure.
abstract: The C-terminal alpha-helix of gp41 membrane-proximal external region (MPER; (671)NWFDITNWLWYIK(683)) encompassing 4E10/10E8 epitopes is an attractive target for HIV-1 vaccine development. We previously reported that gp41-HR1-54Q, a trimeric protein comprised of the MPER in the context of a stable six-helix bundle (6HB), induced strong immune responses against the helix, but antibodies were directed primarily against the non-neutralizing face of the helix. To better target 4E10/10E8 epitopes, we generated four putative fusion intermediates by introducing double point mutations or deletions in the heptad repeat region 1 (HR1) that destabilize 6HB in varying degrees. One variant, HR1-∆10-54K, elicited antibodies in rabbits that targeted W672, I675 and L679, which are critical for 4E10/10E8 recognition. Overall, the results demonstrated that altering structural parameters of 6HB can influence immunogenic properties of the MPER and antibody targeting. Further exploration of this strategy could allow development of immunogens that could lead to induction of 4E10/10E8-like antibodies.
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine; and Center for Advanced Host Defenses, Immunobiotics and Translational Comparative Medicine, Iowa State University, Ames, IA 50011, United States.
authors.forename: Saikat
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine; and Center for Advanced Host Defenses, Immunobiotics and Translational Comparative Medicine, Iowa State University, Ames, IA 50011, United States.
authors.forename: Heliang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine; and Center for Advanced Host Defenses, Immunobiotics and Translational Comparative Medicine, Iowa State University, Ames, IA 50011, United States.
authors.forename: Habtom H
authors.initials: HH
authors.lastname: Habte
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine; and Center for Advanced Host Defenses, Immunobiotics and Translational Comparative Medicine, Iowa State University, Ames, IA 50011, United States.
authors.forename: Yali
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine; and Center for Advanced Host Defenses, Immunobiotics and Translational Comparative Medicine, Iowa State University, Ames, IA 50011, United States. Electronic address: mcho@iastate.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cho
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D017433:Protein Structure, Secondary; D011817:Rabbits
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41
keywords: Fusion intermediate; HIV-1; MPER; gp41