title: Immunogens Modeling a Fusion-Intermediate Conformation of gp41 Elicit Antibodies to the Membrane Proximal External Region of the HIV Envelope Glycoprotein.
abstract: The membrane proximal external region (MPER) of the gp41 subunit of the HIV-1 envelope glycoprotein (Env) contains determinants for broadly neutralizing antibodies and has remained an important focus of vaccine design. However, creating an immunogen that elicits broadly neutralizing antibodies to this region has proven difficult in part due to the relative inaccessibility of the MPER in the native conformation of Env. Here, we describe the antigenicity and immunogenicity of a panel of oligomeric gp41 immunogens designed to model a fusion-intermediate conformation of Env in order to enhance MPER exposure in a relevant conformation. The immunogens contain segments of the gp41 N- and C-heptad repeats to mimic a trapped intermediate, followed by the MPER, with variations that include different N-heptad lengths, insertion of extra epitopes, and varying C-termini. These well-characterized immunogens were evaluated in two different immunization protocols involving gp41 and gp140 proteins, gp41 and gp160 DNA primes, and different immunization schedules and adjuvants. We found that the immunogens designed to reduce extension of helical structure into the MPER elicited the highest MPER antibody binding titers, but these antibodies lacked neutralizing activity. The gp41 protein immunogens also elicited higher MPER titers than the gp140 protein immunogen. In prime-boost studies, the best MPER responses were seen in the groups that received DNA priming with gp41 vectors followed by gp41 protein boosts. Finally, although titers to the entire protein immunogen were similar in the two immunization protocols, MPER-specific titers differed, suggesting that the immunization route, schedule, dose, or adjuvant may differentially influence MPER immunogenicity. These findings inform the design of future MPER immunogens and immunization protocols.
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Russell
authors.initials: R
authors.lastname: Vassell
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Prasad
authors.initials: P
authors.lastname: Vennakalanti
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Antu K
authors.initials: AK
authors.lastname: Dey
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America; Department of Microbiology, Harbin Medical University, Heilongjiang, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhuang
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Yide
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Biron-Sorek
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Indresh K
authors.initials: IK
authors.lastname: Srivastava
authors.affiliation: Department of Surgery, Duke Medical Center, Durham, North Carolina, United States of America.
authors.forename: Celia C
authors.initials: CC
authors.lastname: LaBranche
authors.affiliation: Department of Surgery, Duke Medical Center, Durham, North Carolina, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, Massachusetts, United States of America.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.affiliation: Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Weiss
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D009500:Neutralization Tests; D011487:Protein Conformation; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D014614:Vaccines, Synthetic; D014760:Viral Fusion Proteins