title: Chemically modified peptides based on the membrane-proximal external region of the HIV-1 envelope induce high-titer, epitope-specific nonneutralizing antibodies in rabbits.
abstract: Broadly neutralizing monoclonal antibodies (bNAbs) 2F5 and 4E10 bind to the membrane proximal external region (MPER) of gp41 and also cross-react with phospholipids. In this study, we investigated if chemical modifications on the MPER adjacent to 2F5 and 4E10 epitopes using mimetics of inflammation-associated posttranslational modifications to induce 2F5- and 4E10-like bNAbs can break tolerance. We synthesized a series of chemically modified peptides spanning the MPER. The serine, threonine, and tyrosine residues in the peptides were modified with sulfate, phosphate, or nitrate moieties and presented in liposomes for rabbit immunizations. All immunizations resulted in high antisera titers directed toward both the modified and unmodified immunogens. Tyrosine modification was observed to significantly suppress antiepitope responses. Sera with strong anti-gp140 titers were purified by affinity chromatography toward the MPER peptide and found to possess a higher affinity toward the MPER than did the bNAbs 2F5 and 4E10. Modest neutralization was observed in the H9 neutralization assay, but neutralization was not observed in the TZM-bl cell or peripheral blood mononuclear cell (PBMC) neutralization assay platforms. Although neutralizing antibodies were not induced by this approach, we conclude that chemical modifications can increase the immune responses to poorly immunogenic antigens, suggesting that chemical modification in an appropriate immunization protocol should be explored further as an HIV-1 vaccine strategy.
authors.affiliation: Departments of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Venditto
authors.affiliation: Laboratory of Vaccine Immunology, Walter Reed Army Institute of Research, Military HIV Research Program, Silver Spring, Maryland, USA The Henry M. Jackson Foundation, Bethesda, Maryland, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Wieczorek
authors.affiliation: Laboratory of Vaccine Immunology, Walter Reed Army Institute of Research, Military HIV Research Program, Silver Spring, Maryland, USA The Henry M. Jackson Foundation, Bethesda, Maryland, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Molnar
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Teque
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Landucci
authors.affiliation: Departments of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Watson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Irvine, Irvine, California, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Forthal
authors.affiliation: Laboratory of Vaccine Immunology, Walter Reed Army Institute of Research, Military HIV Research Program, Silver Spring, Maryland, USA.
authors.forename: Victoria R
authors.initials: VR
authors.lastname: Polonis
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Levy
authors.affiliation: Departments of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, San Francisco, California, USA szoka@cgl.ucsf.edu.
authors.forename: Francis C
authors.initials: FC
authors.lastname: Szoka
mesh_terms: D016915:AIDS Vaccines / Q000737:chemistry / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000915:Antibody Affinity / Q000276:immunology; D000080908:Broadly Neutralizing Antibodies; D002460:Cell Line; D002846:Chromatography, Affinity; D003429:Cross Reactions / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D009500:Neutralization Tests; D011817:Rabbits; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: C558560:2F5 monoclonal antibody; D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1