HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Jon M Steichen; Daniel W Kulp; Talar Tokatlian; Amelia Escolano; Pia Dosenovic; Robyn L Stanfield; Laura E McCoy; Gabriel Ozorowski; Xiaozhen Hu; Oleksandr Kalyuzhniy; Bryan Briney; Torben Schiffner; Fernando Garces; Natalia T Freund; Alexander D Gitlin; Sergey Menis; Erik Georgeson; Michael Kubitz; Yumiko Adachi; Meaghan Jones; Andrew A Mutafyan; Dong Soo Yun; Christian T Mayer; Andrew B Ward; Dennis R Burton; Ian A Wilson; Darrell J Irvine; Michel C Nussenzweig; William R Schief

doi:10.1016/j.immuni.2016.08.016

HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Immunity. 2016 Sep 20;45(3):483-496. doi: 10.1016/j.immuni.2016.08.016. Epub 2016 Sep 8.

Authors

Jon M Steichen¹, Daniel W Kulp¹, Talar Tokatlian², Amelia Escolano³, Pia Dosenovic³, Robyn L Stanfield⁴, Laura E McCoy¹, Gabriel Ozorowski⁴, Xiaozhen Hu¹, Oleksandr Kalyuzhniy¹, Bryan Briney¹, Torben Schiffner¹, Fernando Garces⁴, Natalia T Freund³, Alexander D Gitlin³, Sergey Menis¹, Erik Georgeson¹, Michael Kubitz¹, Yumiko Adachi¹, Meaghan Jones¹, Andrew A Mutafyan², Dong Soo Yun², Christian T Mayer³, Andrew B Ward⁴, Dennis R Burton⁵, Ian A Wilson⁶, Darrell J Irvine⁷, Michel C Nussenzweig⁸, William R Schief⁹

Affiliations

¹ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI 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 Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
³ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
⁴ IAVI 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, California, USA.
⁵ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI 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; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.
⁶ IAVI 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, California, USA; Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁷ Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Departments of Biological Engineering and Materials Science & Engineering, MIT, Cambridge, MA 02139, USA.
⁸ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: nussen@mail.rockefeller.edu.
⁹ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI 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; The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA. Electronic address: schief@scripps.edu.

Abstract

Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline-targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens.

Publication types

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

MeSH terms

AIDS Vaccines / immunology*
Amino Acid Sequence
Animals
Antibodies, Neutralizing / immunology*
B-Lymphocytes / immunology
Epitopes / immunology
HIV Antibodies / immunology*
HIV Infections / immunology
HIV-1 / immunology
Immunization / methods
Mice
Mice, Knockout
Mutation / immunology
Polysaccharides / immunology*
Sequence Alignment
env Gene Products, Human Immunodeficiency Virus / immunology

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding