Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding

Daniel W Kulp; Jon M Steichen; Matthias Pauthner; Xiaozhen Hu; Torben Schiffner; Alessia Liguori; Christopher A Cottrell; Colin Havenar-Daughton; Gabriel Ozorowski; Erik Georgeson; Oleksandr Kalyuzhniy; Jordan R Willis; Michael Kubitz; Yumiko Adachi; Samantha M Reiss; Mia Shin; Natalia de Val; Andrew B Ward; Shane Crotty; Dennis R Burton; William R Schief

doi:10.1038/s41467-017-01549-6

Structure-based design of native-like HIV-1 envelope trimers to silence non-neutralizing epitopes and eliminate CD4 binding

Nat Commun. 2017 Nov 21;8(1):1655. doi: 10.1038/s41467-017-01549-6.

Authors

Daniel W Kulp^{1

2

3

4}, Jon M Steichen^{1

2

3}, Matthias Pauthner^{1

2

3}, Xiaozhen Hu^{1

2

3}, Torben Schiffner^{1

2

3}, Alessia Liguori^{1

2

3}, Christopher A Cottrell^{2

3

5}, Colin Havenar-Daughton^{3

6}, Gabriel Ozorowski^{2

3

5}, Erik Georgeson^{1

2

3}, Oleksandr Kalyuzhniy^{1

2

3}, Jordan R Willis^{1

2

3}, Michael Kubitz^{1

2

3}, Yumiko Adachi^{1

2

3}, Samantha M Reiss^{3

6}, Mia Shin^{2

3

5}, Natalia de Val^{2

3

5}, Andrew B Ward^{2

3

5}, Shane Crotty^{3

6

7}, Dennis R Burton^{1

2

3

8}, William R Schief^{9

10

11

12}

Affiliations

¹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
² IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
³ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁴ Vaccine and Immune Therapy Center, The Wistar Institute, Philadelphia, PA, 19104, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁶ Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, 92037, USA.
⁷ Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA, 92037, USA.
⁸ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA.
⁹ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹⁰ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹¹ Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹² The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA. schief@scripps.edu.

Abstract

Elicitation of broadly neutralizing antibodies (bnAbs) is a primary HIV vaccine goal. Native-like trimers mimicking virion-associated spikes present nearly all bnAb epitopes and are therefore promising vaccine antigens. However, first generation native-like trimers expose epitopes for non-neutralizing antibodies (non-nAbs), which may hinder bnAb induction. We here employ computational and structure-guided design to develop improved native-like trimers that reduce exposure of non-nAb epitopes in the V3-loop and trimer base, minimize both CD4 reactivity and CD4-induced non-nAb epitope exposure, and increase thermal stability while maintaining bnAb antigenicity. In rabbit immunizations with native-like trimers of the 327c isolate, improved trimers suppress elicitation of V3-directed and tier-1 neutralizing antibodies and induce robust autologous tier-2 neutralization, unlike a first-generation trimer. The improved native-like trimers from diverse HIV isolates, and the design methods, have promise to assist in the development of a HIV vaccine.

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 / administration & dosage
AIDS Vaccines / chemistry*
AIDS Vaccines / genetics
AIDS Vaccines / immunology*
Animals
Antibodies, Neutralizing / immunology
Antibodies, Viral / immunology*
CD4 Antigens / genetics
CD4 Antigens / immunology*
Epitopes / chemistry
Epitopes / genetics
Epitopes / immunology
Female
HIV Infections / immunology
HIV Infections / virology*
HIV-1 / chemistry
HIV-1 / genetics
HIV-1 / immunology*
Humans
Immunization
Protein Multimerization
Rabbits
env Gene Products, Human Immunodeficiency Virus / administration & dosage
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, Neutralizing
Antibodies, Viral
CD4 Antigens
Epitopes
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding