The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template

Raiees Andrabi; Jesper Pallesen; Joel D Allen; Ge Song; Jinsong Zhang; Natalia de Val; Gavin Gegg; Katelyn Porter; Ching-Yao Su; Matthias Pauthner; Amanda Newman; Hilary Bouton-Verville; Fernando Garces; Ian A Wilson; Max Crispin; Beatrice H Hahn; Barton F Haynes; Laurent Verkoczy; Andrew B Ward; Dennis R Burton

doi:10.1016/j.celrep.2019.04.082

The Chimpanzee SIV Envelope Trimer: Structure and Deployment as an HIV Vaccine Template

Cell Rep. 2019 May 21;27(8):2426-2441.e6. doi: 10.1016/j.celrep.2019.04.082.

Authors

Raiees Andrabi¹, Jesper Pallesen², Joel D Allen³, Ge Song¹, Jinsong Zhang⁴, Natalia de Val⁵, Gavin Gegg¹, Katelyn Porter¹, Ching-Yao Su¹, Matthias Pauthner¹, Amanda Newman⁴, Hilary Bouton-Verville⁴, Fernando Garces⁵, Ian A Wilson⁶, Max Crispin³, Beatrice H Hahn⁷, Barton F Haynes⁸, Laurent Verkoczy⁹, Andrew B Ward¹⁰, Dennis R Burton¹¹

Affiliations

¹ 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; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA.
² International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, 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.
³ International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; School of Biological Sciences, University of Southampton, Southampton, UK.
⁴ Duke Human Vaccine Institute and Departments of Medicine and Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
⁵ 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.
⁶ International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, 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.
⁷ Departments of Medicine and Microbiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Duke Human Vaccine Institute and Departments of Medicine and Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
⁹ Duke Human Vaccine Institute and Departments of Medicine and Immunology, Duke University School of Medicine, Durham, NC 27710, USA; Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA; San Diego Biomedical Research Institute, San Diego, CA 92121, USA.
¹⁰ International AIDS Vaccine Initiative, Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, 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. Electronic address: andrew@scripps.edu.
¹¹ 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; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02114, USA. Electronic address: burton@scripps.edu.

Abstract

Epitope-targeted HIV vaccine design seeks to focus antibody responses to broadly neutralizing antibody (bnAb) sites by sequential immunization. A chimpanzee simian immunodeficiency virus (SIV) envelope (Env) shares a single bnAb site, the variable loop 2 (V2)-apex, with HIV, suggesting its possible utility in an HIV immunization strategy. Here, we generate a chimpanzee SIV Env trimer, MT145K, which displays selective binding to HIV V2-apex bnAbs and precursor versions, but no binding to other HIV specificities. We determine the structure of the MT145K trimer by cryo-EM and show that its architecture is remarkably similar to HIV Env. Immunization of an HIV V2-apex bnAb precursor Ab-expressing knockin mouse with the chimpanzee MT145K trimer induces HIV V2-specific neutralizing responses. Subsequent boosting with an HIV trimer cocktail induces responses that exhibit some virus cross-neutralization. Overall, the chimpanzee MT145K trimer behaves as expected from design both in vitro and in vivo and is an attractive potential component of a sequential immunization regimen to induce V2-apex bnAbs.

Keywords: HIV envelope trimer; HIV vaccine; V2-apex bnAb site; broadly neutralizing antibodies; chimpanzee SIV envelope trimer; glycan shield; human immunodeficiency virus; immunization strategies; simian immunodeficiency virus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

AIDS Vaccines / chemistry*
AIDS Vaccines / immunology
Animals
Antibodies, Neutralizing / immunology
Antigen-Antibody Reactions
Cryoelectron Microscopy
Gene Products, env / chemistry*
Gene Products, env / genetics
Gene Products, env / immunology
Gene Products, env / metabolism
Glycosylation
HIV Antibodies / immunology
Humans
Mice
Mice, Inbred C57BL
Models, Animal
Mutagenesis, Site-Directed
Pan troglodytes / virology
Precursor Cells, B-Lymphoid / cytology
Precursor Cells, B-Lymphoid / immunology
Precursor Cells, B-Lymphoid / metabolism
Protein Engineering
Protein Structure, Quaternary
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / immunology
Simian Immunodeficiency Virus / metabolism*

Substances

AIDS Vaccines
Antibodies, Neutralizing
Gene Products, env
HIV Antibodies
Recombinant Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding