The HIV-1 gp160 trimer is a crucial mediator of viral entry and a primary target in HIV vaccine design, as numerous broadly neutralizing antibodies (bnAbs) target various sites on this trimer [1]. Gp160 is a membrane-anchored complex of gp120–gp41 heterodimers: each gp41 subunit contains the fusion machinery and is tethered to the viral membrane by a transmembrane domain (TMD) and the membrane-proximal external region (MPER) [2]. The full-length gp160 is challenging to study due to low yield, poor stability, and conformational variability [3].

To overcome these challenges, stabilized soluble ectodomain trimers, such as gp140 SOSIP, were designed. The stabilization of SOSIP was achieved by introducing a covalent disulfide bond between gp120 and gp41 (SOS), along with an isoleucine-to-proline substitution (IP) [4,5]. Other stabilized soluble ectodomains, such as IDL (inter-domain lock), have been developed [6]. These trimers recapitulate many antigenic features of gp160 and have enabled high-resolution structural analyses of bnAb epitopes; however, they lack the MPER, TMD, and cytoplasmic tail. SOSIP trimers have not reliably elicited bnAbs in immunization studies, potentially due to differences in conformation or glycosylation patterns [7]. Additionally, both SOSIP and IDL trimers can elicit weakly/non-neutralizing antibodies (nNAbs) directed to the artificial surface (created by gp41 truncation) at the trimer base. Naturally, this surface is hidden and inaccessible in the membrane-anchored gp160.

Detergent-solubilized gp160, while retaining full-length structure, disrupts native trimer conformation and compromises epitope presentation due to the lack of a stabilizing membrane environment. The presence of phospholipids is essential for stabilizing the MPER and improving epitope presentation [8,10]. Additionally, several studies have demonstrated that bnAbs targeting MPER interact not only with the MPER peptide epitope but also with the surrounding lipid bilayer. A recent study by Maillie et al. showed that specific loops within the antibodies' complementarity-determining regions (CDRs) form stable complexes with phospholipid headgroups, effectively anchoring the antibodies to the membrane [10].

Lipid nanodisc technology provides a more efficient platform for structural studies of full-length gp160, offering a native-like membrane environment that preserves the full set of neutralization epitopes, including the MPER and other membrane-proximal elements, in their native geometry [8,9]. Recent cryo-EM studies of gp160 in lipid nanodiscs have resolved the MPER helices at the trimer base and captured the quaternary MPER epitope bound by bnAbs [9··]. These advances are guiding the development of next-generation HIV vaccines to elicit bnAbs that target conserved and vulnerable regions of the native viral gp160.