Temsavir Modulates HIV-1 Envelope Conformation by Decreasing Its Proteolytic Cleavage

HIV-1 envelope glycoproteins (Envs) mediate viral entry and represent a target of choice for small molecule inhibitors. One of them, temsavir (BMS-626529) prevents the interaction of the host cell receptor CD4 with Env by binding the pocket under the beta 20-beta 21 loop of the Env subunit gp120. Along with its capacity to prevent viral entry, temsavir stabilizes Env in its closed conformation. We recently reported that temsavir affects glycosylation, proteolytic processing, and overall conformation of Env. Here, we extend these results to a panel of primary Envs and infectious molecular clones (IMCs), where we observe a heterogeneous impact on Env cleavage and conformation. Our results suggest that the effect of temsavir on Env conformation is associated with its capacity to decrease Env processing. Indeed, we found that the effect of temsavir on Env processing affects the recognition of HIV-1-infected cells by broadly neutralizing antibodies and correlates with their capacity to mediate antibody-dependent cellular cytotoxicity (ADCC).

Automated summary

HIV-1 envelope glycoproteins (Envs) play a crucial role in viral entry and are a preferred target for small molecule inhibitors. Temsavir inhibits the interaction between the host cell receptor CD4 and Env by binding a specific region on the Env subunit gp120. Besides blocking viral entry, temsavir also stabilizes the closed conformation of Env. This study shows that temsavir affects the glycosylation, proteolytic processing, and overall conformation of Env, which in turn impacts the recognition of HIV-1-infected cells by broadly neutralizing antibodies and their ability to mediate antibody-dependent cellular cytotoxicity (ADCC).