The envelope cytoplasmic tail regulates HIV-1 assembly and spread

Abstract

The HIV-1 envelope (Env) is an essential determinant of viral infectivity, tropism and spread between T cells. Lentiviral Env contain an unusually long 150 amino acid cytoplasmic tail (EnvCT) but the function of the EnvCT and conserved domains within it remain largely uncharacterised. Here we identified a highly conserved tryptophan motif at position 757 (W757) in the LLP-2 alpha helix of the EnvCT as a key determinant for HIV-1 replication and spread between T cells. Strikingly we find that mutating W757 had wide-ranging consequences including altering Env mobility in the plasma membrane, preventing Env and Gag recruitment to sites of cell-cell contact for virological synapse (VS) formation and cell-cell spread, and impeding viral fusion. Notably, W757 was also required for efficient virus budding, revealing a previously unappreciated role for the EnvCT in regulating HIV-1 assembly and egress. We conclude that W757 is a key residue that stabilises the structural integrity and function of Env, consistent with the recent model that this region of the EnvCT acts as a critical supporting baseplate for Env.

Functional and structural segregation of overlapping helices in HIV-1

“…In addition to this negative charge, positive charges positioned on the same face of the helix are also important. Previous studies have suggested several possible functions for the LLP-2, including maintaining Env in a prefusogenic state ( Lu et al, 2008 ; Postler and Desrosiers, 2013 ; Murphy et al, 2017 ), regulating viral assembly and egress ( Snetkov et al, 2021 ), or mediating matrix-Env interactions ( Alfadhli et al, 2019 ). The function of these charged residues in viral fusion or assembly remains to be determined.…”