Temsavir blocks the immunomodulatory activities of HIV-1 soluble gp120

While HIV-1-mediated CD4 downregulation protects infected cells from antibody-dependent cellular cyto-toxicity (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. Tem-savir 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 sug-gests that the clinical benefits provided by temsavir could extend beyond blocking viral entry.

Automated summary

While HIV-1-mediated CD4 downregulation protects infected cells from ADCC, shed gp120 binds to uninfected bystander CD4+ T cells, sensitizing them to ADCC mediated by HIV+ plasma and triggering a cytokine burst. Temsavir, an HIV-1 attachment inhibitor, not only prevents gp120-CD4 interaction and alters Env antigenicity, but also blocks the immunomodulatory activities of shed gp120. Temsavir protects uninfected bystander CD4+ cells from ADCC responses and cytokine burst by preventing gp120 interaction, reducing shedding, and altering antigenicity.