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.

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.