Conformational Dynamics of Single HIV-1 Envelope Proteins on the Surface of Native Virions

Abstract

The HIV-1 envelope (Env) mediates viral entry into host cells. While static images of Env in unliganded and ligand-bound forms define distinct conformations, direct observations of Env dynamics have yet to be realized. Here we apply single-molecule fluorescence resonance energy transfer (smFRET) imaging to elucidate the dynamics of native Env trimers on the surface of HIV-1 virions. Our observations indicated that unliganded HIV-1 Env transitions between three distinct pre-fusion conformations, which are affected by the viral receptor and co-receptors. Differences in conformational dynamics and ligand responsiveness of neutralization-sensitive and neutralization-resistant HIV-1 isolates delineated a dynamics-based mechanism of immune evasion. Broadly neutralizing antibodies stabilized one distinct pre-fusion conformation of Env, indicating the importance of the observed dynamics to HIV-1 Env function.