HIV-1 gp160 in nanodiscs: Unravelling structures and guiding vaccine design

The stabilization of HIV-1 gp160 trimers (Env) within phospholipid bilayer nanodiscs has provided critical structural insights into the membrane-proximal external region (MPER) and the broader dynamics of gp160. Cryo-EM and molecular simulations reveal that the membrane context preserves the MPER architecture and captures spontaneous trimer asymmetry, as well as ectodomain tilting. These dynamic properties expose vulnerable epitopes that are targeted by broadly neutralizing antibodies (bnAbs). Studies using nanodiscs have highlighted how interactions with the membrane affect the structure of gp160, the accessibility of epitopes, and the mechanisms of neutralization, providing important insights for immunogen design. Unlike soluble SOSIP and IDL constructs, full-length nanodisc-embedded gp160 maintains its native stability, flexibility, and the complete set of neutralization epitopes, suggesting that membrane-mimicking platforms are essential for the rational design of next-generation HIV vaccines targeting conserved regions, such as the MPER.