Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies

Panpan Zhou; Han Wang; Mengqi Fang; Yangyang Li; Hua Wang; Shasha Shi; Zihao Li; Jiapeng Wu; Xiaoxu Han; Xuanling Shi; Hong Shang; Tongqing Zhou; Linqi Zhang

doi:10.1371/journal.ppat.1007819

Broadly resistant HIV-1 against CD4-binding site neutralizing antibodies

PLoS Pathog. 2019 Jun 13;15(6):e1007819. doi: 10.1371/journal.ppat.1007819. eCollection 2019 Jun.

Authors

Panpan Zhou¹, Han Wang¹, Mengqi Fang¹, Yangyang Li¹, Hua Wang¹, Shasha Shi¹, Zihao Li¹, Jiapeng Wu¹, Xiaoxu Han², Xuanling Shi¹, Hong Shang², Tongqing Zhou³, Linqi Zhang¹

Affiliations

¹ Comprehensive AIDS Research Center, 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, China.
² Key Laboratory of AIDS Immunology of the Ministry of Health, Department of Laboratory Medicine, No. 1 Hospital of China Medical University, Shenyang, China.
³ Vaccine Research Center, National Institute of Allergy and Infectious Diseases and National Institutes of Health, Bethesda, MD, United States of America.

Abstract

Recently identified broadly neutralizing antibodies (bnAbs) show great potential for clinical interventions against HIV-1 infection. However, resistant strains may impose substantial challenges. Here, we report on the identification and characterization of a panel of HIV-1 strains with broad and potent resistance against a large number of bnAbs, particularly those targeting the CD4-binding site (CD4bs). Site-directed mutagenesis revealed that several key epitope mutations facilitate resistance and are located in the inner domain, loop D, and β23/loop V5/β24 of HIV-1 gp120. The resistance is largely correlated with binding affinity of antibodies to the envelope trimers expressed on the cell surface. Our results therefore demonstrate the existence of broadly resistant HIV-1 strains against CD4bs neutralizing antibodies. Treatment strategies based on the CD4bs bnAbs must overcome such resistance to achieve optimal clinical outcomes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibodies, Neutralizing / genetics
Antibodies, Neutralizing / immunology*
CD4 Antigens / genetics
CD4 Antigens / immunology*
Cell Line
Epitopes / genetics
Epitopes / immunology*
HIV Antibodies / genetics
HIV Antibodies / immunology*
HIV Envelope Protein gp120 / genetics
HIV Envelope Protein gp120 / immunology*
HIV-1 / genetics
HIV-1 / immunology*
Humans

Substances

Antibodies, Neutralizing
CD4 Antigens
Epitopes
HIV Antibodies
HIV Envelope Protein gp120
gp120 protein, Human immunodeficiency virus 1

Grants and funding

This study was funded by the National Natural Science Foundation Award (81530065), the National Science and Technology Major Projects (2017ZX10201101 and 2018ZX10731101), Beijing Municipal Science and Technology Commission (171100000517-001 and -003), and Ministry of Science and Technology of China (2014CB542500-03) awarded to Linqi Zhang and Grand Challenges China (81661128042 and OPP1162123) awarded to Linqi Zhang and Tongqing Zhou respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.