Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model

James E Voss; Raiees Andrabi; Laura E McCoy; Natalia de Val; Roberta P Fuller; Terrence Messmer; Ching-Yao Su; Devin Sok; Salar N Khan; Fernando Garces; Laura K Pritchard; Richard T Wyatt; Andrew B Ward; Max Crispin; Ian A Wilson; Dennis R Burton

doi:10.1016/j.celrep.2017.09.024

Elicitation of Neutralizing Antibodies Targeting the V2 Apex of the HIV Envelope Trimer in a Wild-Type Animal Model

Cell Rep. 2017 Oct 3;21(1):222-235. doi: 10.1016/j.celrep.2017.09.024.

Authors

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
² Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Division of Infection and Immunity, Faculty of Medical Science, University College London, London WC1E 6BT, UK.
³ Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁵ Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
⁶ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
⁷ Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁸ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA; Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02114, USA. Electronic address: burton@scripps.edu.

Abstract

Recent efforts toward HIV vaccine development include the design of immunogens that can engage B cell receptors with the potential to affinity mature into broadly neutralizing antibodies (bnAbs). V2-apex bnAbs, which bind a protein-glycan region on HIV envelope glycoprotein (Env) trimer, are among the most broad and potent described. We show here that a rare "glycan hole" at the V2 apex is enriched in HIV isolates neutralized by inferred precursors of prototype V2-apex bnAbs. To investigate whether this feature could focus neutralizing responses onto the apex bnAb region, we immunized wild-type rabbits with soluble trimers adapted from these Envs. Potent autologous tier 2 neutralizing responses targeting basic residues in strand C of the V2 region, which forms the core epitope for V2-apex bnAbs, were observed. Neutralizing monoclonal antibodies (mAbs) derived from these animals display features promising for subsequent broadening of the response.

Keywords: HIV; SOSIP trimer; V2 apex; bnAbs; germline targeting; glycan hole; immunizations; neutralizing antibodies; rabbit; vaccine.

MeSH terms

AIDS Vaccines / administration & dosage
AIDS Vaccines / biosynthesis
AIDS Vaccines / genetics
Amino Acid Sequence
Animals
Antibodies, Monoclonal / biosynthesis*
Antibodies, Monoclonal / chemistry
Antibodies, Neutralizing / biosynthesis*
Antibodies, Neutralizing / chemistry
Antigens, Viral / chemistry
Antigens, Viral / genetics
Antigens, Viral / immunology*
Binding Sites
Epitopes / chemistry
Epitopes / immunology
Female
HIV Antibodies / biosynthesis*
HIV Antibodies / chemistry
HIV Infections / immunology
HIV Infections / prevention & control*
HIV Infections / virology
HIV-1 / chemistry
HIV-1 / genetics
HIV-1 / immunology*
Humans
Immunization
Neutralization Tests
Polysaccharides / chemistry
Polysaccharides / immunology
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Protein Multimerization
Rabbits
env Gene Products, Human Immunodeficiency Virus / chemistry
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

AIDS Vaccines
Antibodies, Monoclonal
Antibodies, Neutralizing
Antigens, Viral
Epitopes
HIV Antibodies
Polysaccharides
env Gene Products, Human Immunodeficiency Virus

Abstract

MeSH terms

Substances

Grants and funding