The HIV-1 envelope spike (Env) is the sole antigen on the virion surface that induces strong antibody responses in infected individuals; it is the key target for B-cell based HIV-1 vaccine development. The full-length Env contains a heavily glycosylated ectodomain, the highly conserved membrane-proximal external region (MPER), a single-pass transmembrane domain (TMD), and a large cytoplasmic tail (CT) of ~150 residues. Multiple lines of evidence suggest that the different regions of the Env are structurally coupled, and thus they all can play a role in modulating the antigenic properties of the Env. Historically, the transmembrane and membrane-proximal regions of single-pass membrane proteins have been difficult to visualize. In this study, we finally managed to solve an NMR structure of the full-length CT using a protein fragment comprising the TMD and the CT in large bicelles that closely mimic a lipid bilayer. By integrating the new NMR data and those acquired previously on other protein fragments, we derived a model of the entire membrane-interacting region of the Env. Moreover, Anne Brown lab of Virginia Tech performed all-atom molecular dynamics (MD) simulations (1 ms) in membrane with HIV lipid composition and showed how the remarkable CT structure can be accommodated in HIV membrane. The results are described in Piai et al, J Am Chem Soc 2021, doi: 10.1021/jacs.1c01762.