The HIV-1 envelope glycoprotein (Env) is the key target of neutralizing antibodies, blocking virus entry. Env is a metastable trimer composed of the receptor binding domain gp120 and the fusion protein subunit gp41. Upon cellular receptor binding Env undergoes a series of conformational changes notably within gp41, which pulls viral and cellular membranes into close proximity to catalyze membrane fusion and initiate infection.
In this article, the EBEV group and collaborators from the University of the Basque Country, the University of Zurich and the University of Lorraine present the crystal structure of gp41 locked in a fusion intermediate state. This structure illustrates the conformational plasticity of the six membrane anchors arranged asymmetrically with the fusion peptides (FP) and the transmembrane regions (TMR) pointing into different directions permitting a close apposition of viral and cellular membranes. Molecular dynamics simulation demonstrates the transition pathway from the intermediate state highlighted by the crystal structure into the final post-fusion conformation. Furthermore, the crystal structure conformation can be targeted by broadly neutralizing antibodies (bnAbs) recognizing the highly conserved membrane proximal external region (MPER). This corroborates that MPER bnAbs can block final steps of refolding of FP and TMR, which is required for completing membrane fusion.
Structure of HIV-1 gp41 with its membrane anchors targeted by neutralizing antibodies. Caillat C, Guilligay D, Torralba J, Friedrich N, Nieva JL, Trkola A, Chipot CJ, Dehez FL, Weissenhorn W. Elife 2021 Apr 19 ;10:e65005
Contact : W. Weissenhorn, UGA professor attached to the IBS (Entry and Budding of Enveloped Viruses Group)