Changes in the V1 Loop of HIV-1 Envelope Glycoproteins Can Allosterically Modulate the Trimer Association Domain and Reduce PGT145 Sensitivity

ACS Infect Dis. 2021 Jun 11;7(6):1558-1568. doi: 10.1021/acsinfecdis.0c00899. Epub 2021 May 18.

Abstract

Human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) are a main focus of immunogen design and vaccine development. Broadly neutralizing antibodies (bnAbs) against HIV-1 Envs target conserved epitopes and neutralize multiple HIV-1 viral strains. Nevertheless, application of bnAbs to therapy and prevention is limited by resistant strains that are developed or preexist within the viral population. Here we studied the HIV-1NAB9 Envs that were isolated from a person who injects drugs and exhibits high and broad resistance to multiple bnAbs. We identified an insertion of 11 amino acids in the V1 loop that allosterically modulates HIV-1NAB9 sensitivity to the PGT145 bnAb, which targets the Env trimer association domain and supports high level viral infectivity. Our data provide new insights into the mechanisms of HIV-1 resistance to bnAbs and into allosteric connectivity between different HIV-1 Env domains.

Keywords: HIV-1; broadly neutralizing antibodies; entry inhibition; envelope glycoproteins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antibodies, Neutralizing / pharmacology*
  • Drug Resistance, Viral / genetics*
  • Glycoproteins
  • HIV Antibodies / pharmacology*
  • HIV-1* / drug effects
  • HIV-1* / genetics
  • Humans
  • env Gene Products, Human Immunodeficiency Virus* / genetics

Substances

  • Antibodies, Neutralizing
  • Glycoproteins
  • HIV Antibodies
  • env Gene Products, Human Immunodeficiency Virus