Gp41-targeted antibodies restore infectivity of a fusion-deficient HIV-1 envelope glycoprotein

PLoS Pathog. 2020 May 11;16(5):e1008577. doi: 10.1371/journal.ppat.1008577. eCollection 2020 May.


The HIV-1 envelope glycoprotein (Env) mediates viral entry via conformational changes associated with binding the cell surface receptor (CD4) and coreceptor (CCR5/CXCR4), resulting in subsequent fusion of the viral and cellular membranes. While the gp120 Env surface subunit has been extensively studied for its role in viral entry and evasion of the host immune response, the gp41 transmembrane glycoprotein and its role in natural infection are less well characterized. Here, we identified a primary HIV-1 Env variant that consistently supports >300% increased viral infectivity in the presence of autologous or heterologous HIV-positive plasma. However, in the absence of HIV-positive plasma, viruses with this Env exhibited reduced infectivity that was not due to decreased CD4 binding. Using Env chimeras and sequence analysis, we mapped this phenotype to a change Q563R, in the gp41 heptad repeat 1 (HR1) region. We demonstrate that Q563R reduces viral infection by disrupting formation of the gp41 six-helix bundle required for virus-cell membrane fusion. Intriguingly, antibodies that bind cluster I epitopes on gp41 overcome this inhibitory effect, restoring infectivity to wild-type levels. We further demonstrate that the Q563R change increases HIV-1 sensitivity to broadly neutralizing antibodies (bNAbs) targeting the gp41 membrane-proximal external region (MPER). In summary, we identify an HIV-1 Env variant with impaired infectivity whose Env functionality is restored through the binding of host antibodies. These data contribute to our understanding of gp41 residues involved in membrane fusion and identify a mechanism by which host factors can alleviate a viral defect.

Publication types

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

MeSH terms

  • Antibodies, Neutralizing / immunology
  • Antibodies, Neutralizing / pharmacology*
  • CD4 Antigens / immunology
  • HEK293 Cells
  • HIV Antibodies / immunology
  • HIV Antibodies / pharmacology*
  • HIV Envelope Protein gp41* / antagonists & inhibitors
  • HIV Envelope Protein gp41* / immunology
  • HIV Infections / drug therapy
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV-1 / immunology*
  • Humans
  • Virus Internalization / drug effects*


  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Antibodies
  • HIV Envelope Protein gp41
  • gp41 protein, Human immunodeficiency virus 1