Conformational Differences between Functional Human Immunodeficiency Virus Envelope Glycoprotein Trimers and...

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• Human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimers mediate viral entry.
• Soluble, stabilized Env trimers (sgp140 SOSIP.664) are potential vaccine candidates.
• Understanding structural differences between membrane-bound and soluble Env is crucial for vaccine development.

Purpose of the Study:

• To compare the conformations of functional membrane-bound HIV-1 Env trimers and stabilized soluble sgp140 SOSIP.664 trimers.
• To identify specific structural differences in gp120 and gp41 subunits.
• To provide constraints for validating structural models of native HIV-1 Env trimers.

Main Methods:

• Cross-linking/mass spectrometry was employed to analyze Env conformations.
• Conformational analysis was performed on both membrane Env and sgp140 SOSIP.664 trimers.
• Accessibility of the gp41 HR1 coiled coil was assessed using a gp41 HR2 peptide.

Main Results:

• Significant differences were observed in the gp120 trimer association domain, C terminus, and the gp41 heptad repeat 1 (HR1) region between membrane Env and sgp140 SOSIP.664.
• Unlike membrane Env, the HR1 coiled coil of sgp140 SOSIP.664 was accessible to the gp41 HR2 peptide even without CD4 binding.
• These findings reveal distinct conformational states of the Env trimer.

Conclusions:

• Stabilized soluble HIV-1 Env trimers exhibit structural differences compared to native membrane-bound Env.
• These differences, particularly in gp120 and gp41 subunits, may influence the immune response.
• The study provides valuable insights for improving the design of HIV-1 Env-based vaccines.