Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein

Abstract

The prefusion conformation of HIV-1 envelope protein (Env) is recognized by most broadly neutralizing antibodies (bnAbs). Studies showed that alterations of its membrane-related components, including the transmembrane domain (TMD) and cytoplasmic tail (CT), can reshape the antigenic structure of the Env ectodomain. Using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of an Env segment encompassing the TMD and a large portion of the CT in bicelles. The structure reveals that the CT folds into amphipathic helices that wrap around the C-terminal end of the TMD, thereby forming a support baseplate for the rest of Env. NMR dynamics measurements provide evidences of dynamic coupling across the TMD between the ectodomain and CT. Pseudovirus-based neutralization assays suggest that CT-TMD interaction preferentially affects antigenic structure near the apex of the Env trimer. These results explain why the CT can modulate the Env antigenic properties and may facilitate HIV-1 Env-based vaccine design.

Cholesterol in the Viral Membrane is a Molecular Switch Governing HIV‐1 Env Clustering

“…We further demonstrated that the region comprising residues 751–854 in the gp41 CT, and in particular the region containing LLP2 and 3, is responsible for the interaction, while LLP1 appears to be dispensable. All three LLP α ‐helixes have membrane‐binding properties [ 38–40 ] and are partially embedded in the inner leaflet of the viral membrane, [ 41–43 ] which supports their role in the interaction of gp41 with chol. Furthermore, previously published work has shown that selective pressure results in HIV‐1 partially overcoming the antiretroviral effect of a chol‐binding compound, amphotericin B methyl ester (AME), by developing truncations in the gp41 CT.…”

“…Specifically, we focused on the role that the three amphipathic α ‐helixes in the CT (known as lentiviral lytic peptides or LLP) may play in the interaction, as they have been described to 1) have membrane‐binding properties [ 38–40 ] and 2) to be partially embedded in the membrane. [ 41–43 ]…”

The envelope cytoplasmic tail regulates HIV-1 assembly and spread

“…Structural insights of the EnvCT by solution state NMR revealed that much of the EnvCT associates closely with cellular membranes, and W757 at the start of the first alpha helix (LLP-2) in the EnvCT appears to provide a crucial anchor point in order to regulate membrane diffusion ( Supplementary Fig. 5) (Murphy et al, 2017;Piai et al, 2020). Perturbation of this W757 anchor point may lead to changes in the quaternary structure of the putative LLP-2 baseplate and could explain an increase in PM diffusivity of the W757A mutant Env trimer compared to the native EnvCT (Piai et al, 2020).…”

“…5) (Murphy et al, 2017;Piai et al, 2020). Perturbation of this W757 anchor point may lead to changes in the quaternary structure of the putative LLP-2 baseplate and could explain an increase in PM diffusivity of the W757A mutant Env trimer compared to the native EnvCT (Piai et al, 2020). Disruption of the EnvCT baseplate by W757A may not just affect membrane diffusion, but could also alter interactions of the EnvCT with host cell proteins or underlying cytoskeleton machinery that are required for polarised recruitment of Env to the VS (Jolly et al, 2004).…”

Immunogenic SARS-CoV-2 Epitopes: In Silico Study Towards Better Understanding of COVID-19 Disease—Paving the Way for Vaccine Development

“…This still needs to be answered. The latter “sword” is known to be avoided at least by HIV, which has a sophisticated mechanism to limit the infection rate in order to better avoid immune surveillance [ 56 , 57 ].…”