A Single Substitution in gp41 Modulates the Neutralization Profile of SHIV during In Vivo Adaptation

Qian Wang; Lihong Liu; Wuze Ren; Agegnehu Gettie; Hua Wang; Qingtai Liang; Xuanling Shi; David C Montefiori; Tongqing Zhou; Linqi Zhang

doi:10.1016/j.celrep.2019.04.108

A Single Substitution in gp41 Modulates the Neutralization Profile of SHIV during In Vivo Adaptation

Cell Rep. 2019 May 28;27(9):2593-2607.e5. doi: 10.1016/j.celrep.2019.04.108.

Authors

Affiliations

¹ Comprehensive AIDS Research Center, 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 100084, China.
² Aaron Diamond AIDS Research Center, 455 First Ave., 7th Floor, New York, NY 10016, USA.
³ Duke Human Vaccine Institute and Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
⁴ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
⁵ Comprehensive AIDS Research Center, 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 100084, China. Electronic address: zhanglinqi@tsinghua.edu.cn.

PMID: 31141685
DOI: 10.1016/j.celrep.2019.04.108

Abstract

The HIV-1 envelope glycoprotein (Env) maintains a delicate balance between mediating viral entry and escaping antibody neutralization. Adaptation during transmission of neutralization-sensitive Envs with an "open" conformation remains poorly understood. By passaging a replication-competent simian-human immunodeficiency virus carrying a highly neutralization-sensitive Env (SHIV_CNE40) in rhesus macaques, we show that SHIV_CNE40 develops enhanced replication kinetics associated with neutralization resistance against antibodies and autologous serum. A gp41 substitution, E658K, functions as the major determinant for these properties. Structural modeling and functional verification indicate that the substitution disrupts an intermolecular salt bridge with the neighboring protomer, thereby promoting fusion and facilitating immune evasion. This effect is applicable across diverse HIV-1 subtypes. Our results highlight the critical role of gp41 in shaping the neutralization profile and the overall conformation of Env during viral adaptation. The unique intermolecular salt bridge could potentially be utilized for rational vaccine design involving more stable HIV-1 envelope trimers.

Keywords: HIV-1; HR2; SHIV; bnAbs; closed conformation; envelope trimer; gp41; neutralizing antibody; open conformation; structure.

Publication types

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

MeSH terms

Adaptation, Physiological*
Amino Acid Substitution
Animals
Antibodies, Neutralizing / immunology*
Female
HIV Antibodies / immunology*
HIV Envelope Protein gp41 / genetics
HIV Envelope Protein gp41 / immunology*
HIV Envelope Protein gp41 / metabolism
Humans
Immune Evasion
Macaca mulatta
Mutation
Neutralization Tests
Protein Conformation
Simian Acquired Immunodeficiency Syndrome / immunology
Simian Acquired Immunodeficiency Syndrome / pathology
Simian Acquired Immunodeficiency Syndrome / virology*
Simian Immunodeficiency Virus / immunology*
Simian Immunodeficiency Virus / physiology
Virus Internalization*

Substances

Antibodies, Neutralizing
HIV Antibodies
HIV Envelope Protein gp41