Stabilized diverse HIV-1 envelope trimers for vaccine design

Qian Wang; Bingting Ma; Qingtai Liang; Angqi Zhu; Hua Wang; Lili Fu; Xiaoxu Han; Xuanling Shi; Ye Xiang; Hong Shang; Linqi Zhang

doi:10.1080/22221751.2020.1745093

Stabilized diverse HIV-1 envelope trimers for vaccine design

Emerg Microbes Infect. 2020 Dec;9(1):775-786. doi: 10.1080/22221751.2020.1745093.

Authors

Qian Wang^{1

2}, Bingting Ma³, Qingtai Liang¹, Angqi Zhu¹, Hua Wang¹, Lili Fu¹, Xiaoxu Han⁴, Xuanling Shi¹, Ye Xiang³, Hong Shang⁴, Linqi Zhang¹

Affiliations

¹ Comprehensive AIDS Research Center and Center for Global Health and Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
² Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Department of Microbiology, Harvard Medical School, Boston, MA, USA.
³ Center for Global Health and Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing, People's Republic of China.
⁴ Key Laboratory of AIDS Immunology of the Ministry of Health, Department of Laboratory Medicine, No. 1 Hospital of China Medical University, Shenyang, People's Republic of China.

Abstract

One of the major goals in HIV-1 vaccine development is to achieve properly folded and stabilized envelope glycoprotein (Env) trimers that mimic the native Env on the mature virion. Here, we design and characterize uncleaved prefusion-optimized (UFO) trimers for 12 Envs currently circulating in China. Biochemical and biophysical characterization of these UFO trimers identified two subtype B/B' Envs, CNE6 and MG13, which exhibited the highest trimer content and stability at a level comparable to the subtype A reference, BG505. Replacing the gp41 ectodomain (gp41_ECTO) of CRF01_AE trimers with that of CNE6, MG13, and BG505 resulted in chimeric constructs with significantly improved trimer content and stability. Negative-stain electron microscopy (EM) confirmed the structural integrity of these chimeric UFO trimers with CNE6 gp41_ECTO. Antibody binding assays showed that the chimeric trimers shared similar antigenic profiles to those with their original gp41_ECTO domains. Our results thus revealed the intrinsic differences among HIV-1 Envs of diverse origins and the critical role of gp41_ECTO in stabilizing the trimeric spike. By taking advantage of naturally stable Envs, gp41_ECTO swapping may represent a universal approach for the generation of stable trimers with the desired structural and antigenic properties for downstream in vivo evaluation and vaccine development.

Keywords: HIV-1 Env; SOSIP trimer; subtype CRF01_AE; uncleaved prefusion-optimized (UFO) trimer; vaccine design.

MeSH terms

AIDS Vaccines / immunology*
Antibodies, Neutralizing / immunology
Binding Sites, Antibody
Drug Design
HIV Antibodies / immunology*
HIV-1
Humans
Immunogenicity, Vaccine
Protein Multimerization / immunology*
env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

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

Grants and funding

This study was funded by the National Natural Science Foundation of China [81530065], the National Science and Technology Major Projects [2017ZX10201101, 2018ZX10731101 and 2018ZX10302-102], Beijing Municipal Science and Technology Commission [171100000517-001 and -003], and Grand Challenges China [81661128042].