Small CD4 Mimetics Prevent HIV-1 Uninfected Bystander CD4 + T Cell Killing Mediated by Antibody-dependent Cell-mediated Cytotoxicity

EBioMedicine. 2015 Dec 9;3:122-134. doi: 10.1016/j.ebiom.2015.12.004. eCollection 2016 Jan.


Human immunodeficiency virus type 1 (HIV-1) infection causes a progressive depletion of CD4 + T cells. Despite its importance for HIV-1 pathogenesis, the precise mechanisms underlying CD4 + T-cell depletion remain incompletely understood. Here we make the surprising observation that antibody-dependent cell-mediated cytotoxicity (ADCC) mediates the death of uninfected bystander CD4 + T cells in cultures of HIV-1-infected cells. While HIV-1-infected cells are protected from ADCC by the action of the viral Vpu and Nef proteins, uninfected bystander CD4 + T cells bind gp120 shed from productively infected cells and are efficiently recognized by ADCC-mediating antibodies. Thus, gp120 shedding represents a viral mechanism to divert ADCC responses towards uninfected bystander CD4 + T cells. Importantly, CD4-mimetic molecules redirect ADCC responses from uninfected bystander cells to HIV-1-infected cells; therefore, CD4-mimetic compounds might have therapeutic utility in new strategies aimed at specifically eliminating HIV-1-infected cells.

Keywords: ADCC; Bystander killing; CD4; CD4-bound conformation; CD4-mimetics; Envelope glycoproteins; HIV-1; Non-neutralizing antibodies; gp120.

Publication types

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

MeSH terms

  • Antibody-Dependent Cell Cytotoxicity / immunology*
  • CD4 Antigens / metabolism*
  • CD4-Positive T-Lymphocytes / physiology*
  • CD4-Positive T-Lymphocytes / virology*
  • Cell Communication
  • Cell Line
  • HIV Envelope Protein gp120 / immunology
  • HIV Envelope Protein gp120 / metabolism
  • HIV-1 / physiology*
  • Humans
  • Molecular Mimicry*
  • Protein Binding


  • CD4 Antigens
  • HIV Envelope Protein gp120