CD4 mimetics sensitize HIV-1-infected cells to ADCC

Jonathan Richard, Maxime Veillette, Nathalie Brassard, Shilpa S. Iyer, Michel Roger, Loïc Martin, Marzena Pazgier, Arne Schön, Ernesto Freire, Jean Pierre Routy, Amos B. Smith, Jongwoo Park, David M. Jones, Joel R. Courter, Bruno N. Melillo, Daniel E. Kaufmann, Beatrice H. Hahn, Sallie R. Permar, Barton F. Haynes, Navid MadaniJoseph G. Sodroski, Andrés Finzi

Research output: Contribution to journalArticle

Abstract

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

Original languageEnglish (US)
Pages (from-to)E2687-E2694
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number20
DOIs
StatePublished - May 19 2015

Keywords

  • ADCC
  • CD4 mimetics
  • Envelope glycoproteins
  • HIV-1
  • gp120

ASJC Scopus subject areas

  • General

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  • Cite this

    Richard, J., Veillette, M., Brassard, N., Iyer, S. S., Roger, M., Martin, L., Pazgier, M., Schön, A., Freire, E., Routy, J. P., Smith, A. B., Park, J., Jones, D. M., Courter, J. R., Melillo, B. N., Kaufmann, D. E., Hahn, B. H., Permar, S. R., Haynes, B. F., ... Finzi, A. (2015). CD4 mimetics sensitize HIV-1-infected cells to ADCC. Proceedings of the National Academy of Sciences of the United States of America, 112(20), E2687-E2694. https://doi.org/10.1073/pnas.1506755112