Conformational dynamics of single HIV-1 envelope trimers on the surface of native virions

HIV's shape-shifting envelope protein HIV's envelope protein (Env) coats virus particles and allows HIV to enter host cells. HIV entry is highly dynamic. Env proteins work in groups of three (called trimers), which bind to the viral receptor and co-receptor, both expressed by host cells. Viral receptor binding causes a structural rearrangement in the trimer that allows for co-receptor binding and finally, viral entry. To visualize dynamic changes in Env conformation during viral entry, Munro et al. added differently colored fluorescent tags to two different regions of individual HIV trimers. Single-molecule fluorescence resonance entry transfer revealed three distinct Env conformations before cell entry. Occupation of particular conformations depended on host receptor binding. Science, this issue p. 759 Single-molecule fluorescence studies reveal how HIV’s viral spike protein varies its conformation as it binds to receptors. The HIV-1 envelope (Env) mediates viral entry into host cells. To enable the direct imaging of conformational dynamics within Env, we introduced fluorophores into variable regions of the glycoprotein gp120 subunit and measured single-molecule fluorescence resonance energy transfer within the context of native trimers on the surface of HIV-1 virions. Our observations revealed unliganded HIV-1 Env to be intrinsically dynamic, transitioning between three distinct prefusion conformations, whose relative occupancies were remodeled by receptor CD4 and antibody binding. The distinct properties of neutralization-sensitive and neutralization-resistant HIV-1 isolates support a dynamics-based mechanism of immune evasion and ligand recognition.