CD4-induced activation in a soluble HIV-1 Env trimer

Area of Science:

• Structural Biology
• Virology
• Biochemistry

Background:

• The HIV envelope glycoprotein (Env) trimer mediates viral entry by undergoing conformational changes upon receptor binding.
• Previous studies using low-resolution electron microscopy revealed large-scale Env rearrangements, but detailed structural dynamics remained unclear.

Purpose of the Study:

• To precisely understand the conformational changes in unliganded and CD4-bound soluble HIV Env trimers (SOSIP.664) using advanced biophysical techniques.
• To investigate the distinct effects of CD4 binding site-targeted inhibitors on Env structure and allosteric pathways.

Main Methods:

• Utilized hydrogen-deuterium exchange mass spectrometry (HDX-MS) and oxidative labeling.
• Analyzed the structural dynamics of soluble Env trimers (SOSIP.664) in unliganded and CD4-bound states.
• Assessed the impact of inhibitors NBD-556 and BMS-806 on Env conformation.

Main Results:

• CD4 binding triggers significant reorganization of Env, including bridging sheet elements, V1/V2 and V3 loops, gp120 inner domain, and the gp41 fusion subunit.
• The inhibitor NBD-556 partially mimics CD4-induced destabilization of the V1/V2 and V3 regions.
• BMS-806 exhibits a more localized effect, primarily impacting the gp120/gp41 interface.

Conclusions:

• Provides high-resolution structural insights into CD4-mediated allosteric changes in the HIV Env trimer.
• Demonstrates differential mechanisms of action for CD4 binding site inhibitors, informing future drug design.
• Enhances understanding of the structural pathways leading to HIV membrane fusion.