AI Article Synopsis
- HIV-1 downregulates CD4 on infected cells to evade antibody-dependent cellular cytotoxicity (ADCC), but shed gp120 can bind CD4 on uninfected bystander T cells, making them more susceptible to ADCC and causing cytokine release.
- Temsavir is a small molecule that inhibits HIV-1 by blocking the interaction between envelope glycoprotein (Env) and CD4, impacting Env's processing and glycosylation.
- In addition to its antiviral effects, temsavir also prevents shed gp120 from interacting with uninfected T cells, thus reducing their vulnerability to ADCC and preventing harmful cytokine bursts, suggesting broader clinical benefits.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198848 | PMC |
| http://dx.doi.org/10.1016/j.chembiol.2023.03.003 | DOI Listing |
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