Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120

Jonathan Richard, Jérémie Prévost, Catherine Bourassa, Nathalie Brassard, Marianne Boutin, Mehdi Benlarbi, Guillaume Goyette, Halima Medjahed, Gabrielle Gendron-Lepage, Fleur Gaudette, Hung Ching Chen, William D. Tolbert, Amos B. Smith, Marzena Pazgier, Mathieu Dubé, Andrew Clark, Walther Mothes, Daniel E. Kaufmann, Andrés Finzi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

While HIV-1-mediated CD4 downregulation protects infected cells from antibody-dependent cellular cytotoxicity (ADCC), shed gp120 binds to CD4 on uninfected bystander CD4+ T cells, sensitizing them to ADCC mediated by HIV+ plasma. Soluble gp120-CD4 interaction on multiple immune cells also triggers a cytokine burst. The small molecule temsavir acts as an HIV-1 attachment inhibitor by preventing envelope glycoprotein (Env)-CD4 interaction and alters the overall antigenicity of Env by affecting its processing and glycosylation. Here we show that temsavir also blocks the immunomodulatory activities of shed gp120. Temsavir prevents shed gp120 from interacting with uninfected bystander CD4+ cells, protecting them from ADCC responses and preventing a cytokine burst. Mechanistically, this depends on temsavir's capacity to prevent soluble gp120-CD4 interaction, to reduce gp120 shedding, and to alter gp120 antigenicity. This suggests that the clinical benefits provided by temsavir could extend beyond blocking viral entry.

Original languageEnglish
Pages (from-to)540-552.e6
JournalCell Chemical Biology
Volume30
Issue number5
DOIs
StatePublished - 18 May 2023
Externally publishedYes

Keywords

  • ADCC
  • BMS-626529
  • BMS-663068
  • Env glycoprotein
  • HIV-1
  • attachment inhibitors
  • cytokine burst
  • fostemsavir
  • soluble gp120
  • temsavir

Fingerprint

Dive into the research topics of 'Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120'. Together they form a unique fingerprint.

Cite this