Disruption of the HIV-1 Envelope allosteric network blocks CD4-induced rearrangements

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• The HIV-1 Envelope protein (Env) is crucial for viral entry, mediating fusion through complex conformational changes.
• Allosteric regulation within Env controls the exposure of binding sites for host receptors.

Purpose of the Study:

• To investigate the molecular mechanisms of allostery in the HIV-1 BG505 Env trimer.
• To identify mutations that block CD4-induced conformational transitions.

Main Methods:

• Introduction of specific mutations into the BG505 Env trimer.
• Binding assays and single-molecule Förster Resonance Energy Transfer (smFRET) to analyze conformational changes.
• Single-particle cryo-electron microscopy (cryo-EM) for structural determination.

Main Results:

• Mutations successfully prevented CD4-induced conformational transitions in the HIV-1 Env trimer.
• Cryo-EM revealed rearrangements in gp120-gp41 interactions within the mutant Env proteins.
• Displacement of tryptophan W571 from its pocket rendered Env insensitive to CD4 binding, highlighting its role as a conformational switch.

Conclusions:

• W571 acts as a critical conformational switch in Env allostery and receptor-mediated viral entry.
• Understanding these Env conformations provides valuable insights for developing effective HIV vaccines.