title: Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry.
abstract: Structural characterization of epitope-paratope pairs has contributed to the understanding of antigenicity. By contrast, few structural studies relate to immunogenicity, the process of antigen-induced immune responses in vivo. Using a lipid-arrayed membrane-proximal external region (MPER) of HIV-1 glycoprotein 41 as a model antigen, we investigated the influence of physicochemical properties on immunogenicity in relation to structural modifications of MPER/liposome vaccines. Anchoring the MPER to the membrane via an alkyl tail or transmembrane domain retained the MPER on liposomes in vivo, while preserving MPER secondary structure. However, structural modifications that affected MPER membrane orientation and antigenic residue accessibility strongly impacted induced antibody responses. The solvent-exposed MPER tryptophan residue (Trp-680) was immunodominant, focusing immune responses, despite sequence variability elsewhere. Nonetheless, immunogenicity could be readily manipulated using site-directed mutagenesis or structural constraints to modulate amino acid surface display. These studies provide fundamental insights for immunogen design aimed at targeting B cell antibody responses.
authors.affiliation: From the Laboratory of Immunobiology and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
authors.forename: Mikyung
authors.initials: M
authors.lastname: Kim
authors.forename: Likai
authors.initials: L
authors.lastname: Song
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.forename: Zhen-Yu J
authors.initials: ZY
authors.lastname: Sun
authors.forename: Anna
authors.initials: A
authors.lastname: Bershteyn
authors.forename: Melissa
authors.initials: M
authors.lastname: Hanson
authors.forename: Derek
authors.initials: D
authors.lastname: Cain
authors.forename: Selasie
authors.initials: S
authors.lastname: Goka
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: Darrell
authors.initials: D
authors.lastname: Irvine
authors.forename: Ellis L
authors.initials: EL
authors.lastname: Reinherz
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000956:Antigens, Viral / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D000956:Antigens, Viral; D018985:Epitopes, B-Lymphocyte; D015700:HIV Envelope Protein gp41; D010455:Peptides; C514787:gp41 protein, Human immunodeficiency virus 1
keywords: Antibodies; HIV-1; Immunodominance; Immunogenicity; Infectious Diseases; Protein Structure; Vaccine Development
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