Conformational changes induced in the human immunodeficiency virus envelope glycoprotein by soluble CD4 binding

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Human immunodeficiency virus (HIV) infects CD4+ T lymphocytes by binding to CD4 receptors via its gp120 envelope glycoprotein.
• Viral entry involves fusion of the virus membrane with the host cell membrane, a process mediated by viral glycoproteins.
• Syncytia formation between HIV-infected and uninfected CD4+ cells also involves cell-cell fusion.

Purpose of the Study:

• To model the molecular events following HIV envelope glycoprotein binding to CD4.
• To investigate conformational changes induced by soluble CD4 (sCD4) interaction with gp120.
• To elucidate the role of these changes in subsequent membrane fusion.

Main Methods:

• Utilized a soluble, recombinant form of CD4 (sCD4) as a model system.
• Assessed conformational changes by antibody binding to gp120/V3 loops on HIV-1-infected cells.
• Measured increased V3 loop cleavage by proteinase on virions.
• Monitored gp41 epitope exposure at different temperatures (4°C and 37°C).

Main Results:

• Complexing sCD4 with gp120 induced conformational changes in envelope glycoprotein oligomers.
• These changes correlated with increased antibody binding to gp120/V3 loops and enhanced V3 loop proteinase cleavage.
• At 37°C, gp120 dissociated from gp41, exposing gp41 epitopes; this dissociation did not occur at 4°C.
• At 4°C, both gp120/V3 and gp41 epitopes were exposed, indicating conformational alterations.

Conclusions:

• CD4 binding to HIV envelope glycoproteins initiates conformational changes essential for membrane fusion.
• The dissociation of gp120 from gp41 and subsequent gp41 exposure are critical steps in the fusion process.
• Temperature-dependent epitope exposure provides insights into the dynamics of HIV-CD4+ cell membrane fusion.