Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120

• Published in: Cell chemical biology Vol. 30; no. 5; pp. 540 - 552.e6
• Main Authors: Richard, Jonathan, Prévost, Jérémie, Bourassa, Catherine, Brassard, Nathalie, Boutin, Marianne, Benlarbi, Mehdi, Goyette, Guillaume, Medjahed, Halima, Gendron-Lepage, Gabrielle, Gaudette, Fleur, Chen, Hung-Ching, Tolbert, William D., Smith, Amos B., Pazgier, Marzena, Dubé, Mathieu, Clark, Andrew, Mothes, Walther, Kaufmann, Daniel E., Finzi, Andrés
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 18.05.2023
• Subjects: ADCC; attachment inhibitors; BMS-626529; BMS-663068; CD4-Positive T-Lymphocytes - metabolism; cytokine burst; Cytokines - metabolism; Down-Regulation; Env glycoprotein; fostemsavir; HIV Envelope Protein gp120; HIV-1; soluble gp120; temsavir; HIV-1; BMS-663068; soluble gp120; temsavir; attachment inhibitors; BMS-626529; fostemsavir; cytokine burst; Env glycoprotein; ADCC
• ISSN: 2451-9456; 2451-9448; 2451-9456
• DOI: 10.1016/j.chembiol.2023.03.003

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. [Display omitted] •Temsavir prevents shed gp120 from interacting with uninfected bystander CD4+ cells•This protects uninfected cells from ADCC responses and prevents a cytokine burst•Temsavir reduces gp120-CD4 interaction and gp120 shedding•Temsavir alters soluble gp120 antigenicity Richard et al. provide extensive evidence suggesting that treatment with the HIV-1 attachment inhibitor temsavir can have beneficial effects that extend beyond viral neutralization, notably by preventing elimination of uninfected cells and induction of a cytokine burst caused by its soluble viral glycoprotein.