HIV-1 Envelope Glycoproteins Proteolytic Cleavage Protects Infected Cells from ADCC Mediated by Plasma from Infected Individuals

Viruses. 2021 Nov 6;13(11):2236. doi: 10.3390/v13112236.


The HIV-1 envelope glycoprotein (Env) is synthesized in the endoplasmic reticulum as a trimeric gp160 precursor, which requires proteolytic cleavage by a cellular furin protease to mediate virus-cell fusion. Env is conformationally flexible but controls its transition from the unbound "closed" conformation (State 1) to downstream CD4-bound conformations (States 2/3), which are required for fusion. In particular, HIV-1 has evolved several mechanisms that reduce the premature "opening" of Env which exposes highly conserved epitopes recognized by non-neutralizing antibodies (nnAbs) capable of mediating antibody-dependent cellular cytotoxicity (ADCC). Env cleavage decreases its conformational transitions favoring the adoption of the "closed" conformation. Here we altered the gp160 furin cleavage site to impair Env cleavage and to examine its impact on ADCC responses mediated by plasma from HIV-1-infected individuals. We found that infected primary CD4+ T cells expressing uncleaved, but not wildtype, Env are efficiently recognized by nnAbs and become highly susceptible to ADCC responses mediated by plasma from HIV-1-infected individuals. Thus, HIV-1 limits the exposure of uncleaved Env at the surface of HIV-1-infected cells at least in part to escape ADCC responses.

Keywords: ADCC; CD4 mimetics; Env glycoprotein; HIV+ plasma; HIV-1; Temsavir; furin cleavage site; nnAbs.

Publication types

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

MeSH terms

  • Amino Acid Motifs
  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • Cell Membrane / metabolism
  • HIV Antibodies / immunology
  • HIV Envelope Protein gp160 / chemistry
  • HIV Envelope Protein gp160 / genetics
  • HIV Envelope Protein gp160 / metabolism
  • HIV Infections / immunology*
  • HIV-1 / immunology*
  • HIV-1 / metabolism
  • Humans
  • Mutation
  • Protein Conformation
  • Proteolysis
  • Virion / immunology
  • Virion / metabolism
  • env Gene Products, Human Immunodeficiency Virus / chemistry
  • env Gene Products, Human Immunodeficiency Virus / genetics
  • env Gene Products, Human Immunodeficiency Virus / metabolism*


  • HIV Antibodies
  • HIV Envelope Protein gp160
  • env Gene Products, Human Immunodeficiency Virus
  • gp160 protein, Human immunodeficiency virus 1