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

doi:10.1016/j.chembiol.2023.03.003

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 journal › Article › peer-review

8 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 language	English
Pages (from-to)	540-552.e6
Journal	Cell Chemical Biology
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.chembiol.2023.03.003
State	Published - 18 May 2023
Externally published	Yes

Keywords

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

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10.1016/j.chembiol.2023.03.003

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Richard, J., Prévost, J., Bourassa, C., Brassard, N., Boutin, M., Benlarbi, M., Goyette, G., Medjahed, H., Gendron-Lepage, G., Gaudette, F., Chen, H. C., Tolbert, W. D., Smith, A. B., Pazgier, M., Dubé, M., Clark, A., Mothes, W., Kaufmann, D. E., & Finzi, A. (2023). Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120. Cell Chemical Biology, 30(5), 540-552.e6. https://doi.org/10.1016/j.chembiol.2023.03.003

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title = "Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120",

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.",

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month = may,

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doi = "10.1016/j.chembiol.2023.03.003",

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Richard, J, Prévost, J, Bourassa, C, Brassard, N, Boutin, M, Benlarbi, M, Goyette, G, Medjahed, H, Gendron-Lepage, G, Gaudette, F, Chen, HC, Tolbert, WD, Smith, AB, Pazgier, M, Dubé, M, Clark, A, Mothes, W, Kaufmann, DE & Finzi, A 2023, 'Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120', Cell Chemical Biology, vol. 30, no. 5, pp. 540-552.e6. https://doi.org/10.1016/j.chembiol.2023.03.003

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T1 - Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120

AU - Richard, Jonathan

AU - Prévost, Jérémie

AU - Bourassa, Catherine

AU - Brassard, Nathalie

AU - Boutin, Marianne

AU - Benlarbi, Mehdi

AU - Goyette, Guillaume

AU - Medjahed, Halima

AU - Gendron-Lepage, Gabrielle

AU - Gaudette, Fleur

AU - Chen, Hung Ching

AU - Tolbert, William D.

AU - Smith, Amos B.

AU - Pazgier, Marzena

AU - Dubé, Mathieu

AU - Clark, Andrew

AU - Mothes, Walther

AU - Kaufmann, Daniel E.

AU - Finzi, Andrés

PY - 2023/5/18

Y1 - 2023/5/18

N2 - 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.

AB - 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.

KW - ADCC

KW - BMS-626529

KW - BMS-663068

KW - Env glycoprotein

KW - HIV-1

KW - attachment inhibitors

KW - cytokine burst

KW - fostemsavir

KW - soluble gp120

KW - temsavir

UR - http://www.scopus.com/inward/record.url?scp=85158918288&partnerID=8YFLogxK

U2 - 10.1016/j.chembiol.2023.03.003

DO - 10.1016/j.chembiol.2023.03.003

M3 - Article

C2 - 36958337

AN - SCOPUS:85158918288

SN - 2451-9456

VL - 30

SP - 540-552.e6

JO - Cell Chemical Biology

JF - Cell Chemical Biology

IS - 5

ER -

Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120

Abstract

Keywords

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