title: Comparison of neutralizing antibody responses elicited from highly diverse polyvalent heterotrimeric HIV-1 gp140 cocktail immunogens versus a monovalent counterpart in rhesus macaques.
abstract: Eliciting neutralizing antibodies capable of inactivating a broad spectrum of HIV-1 strains is a major goal of HIV-1 vaccine design. The challenge is that envelopes (Envs) of circulating viruses are almost certainly different from any Env used in a vaccine. A novel immunogen composed of a highly diverse set of gp140 Envs including subtypes A, B, C, D and F was developed to stimulate a more cross-neutralizing antibody response. Env heterotrimers composed of up to 54 different gp140s were produced with the aim of focusing the response to the conserved regions of Env while reducing the dominance of any individual hypervariable region. Heterotrimeric gp140 Envs of inter- and intra-subtype combinations were shown to bind CD4 and a panel of neutralizing monoclonal antibodies with similar affinity to monovalent UG37 gp140. Macaques immunized with six groups of heterotrimer mixtures showed slightly more potent neutralizing antibody responses in TZM-BL tier 1 and A3R5 tier 2 pseudovirus assays than macaques immunized with monovalent Env gp140, and exhibited a marginally greater focus on the CD4-binding site. Carbopol enhanced neutralization when used as an adjuvant instead of RIBI in combination with UG37 gp140. These data indicate that cross-subtype heterotrimeric gp140 Envs may elicit some improvement of the neutralizing antibody response in macaques compared to monovalent gp140 Env.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Bowles
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Torben
authors.initials: T
authors.lastname: Schiffner
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Maximillian
authors.initials: M
authors.lastname: Rosario
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Gemma A
authors.initials: GA
authors.lastname: Needham
authors.affiliation: Division of Retrovirology, Centre for AIDS Reagents, National Institute of Biological Standards and Control, South Mimms, Potters Bar, Herts, United Kingdom.
authors.forename: Meghna
authors.initials: M
authors.lastname: Ramaswamy
authors.affiliation: Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Joanna
authors.initials: J
authors.lastname: McGouran
authors.affiliation: Henry Wellcome Building for Molecular Physiology, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Kessler
authors.affiliation: Division of Surgical Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McMichael
authors.affiliation: Division of Surgical Sciences, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Quentin J
authors.initials: QJ
authors.lastname: Sattentau
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom; The Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, United Kingdom.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Hanke
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, The John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Guillaume B E
authors.initials: GB
authors.lastname: Stewart-Jones
mesh_terms: D016915:AIDS Vaccines; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000917:Antibody Formation; D015497:HIV-1 / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology*; D009500:Neutralization Tests; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1