CD4 activation of HIV fusion

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Human immunodeficiency viruses (HIV-1 and HIV-2) primarily infect CD4+ cells.
• Viral entry initiates via high-affinity binding between CD4 and the HIV envelope glycoprotein gp120.
• Soluble CD4 (sCD4) systems enable analysis of binding kinetics, thermodynamics, and fusion events.

Purpose of the Study:

• To analyze the interaction between CD4 and HIV gp120.
• To investigate the post-binding events leading to virus-cell membrane fusion.
• To understand the mechanism of receptor-mediated activation of HIV fusion.

Main Methods:

• Utilized soluble recombinant CD4 (sCD4) to study gp120 binding.
• Analyzed kinetic and thermodynamic properties of CD4-gp120 interactions.
• Investigated conformational changes in gp120 and gp41 upon sCD4 binding.

Main Results:

• sCD4 binding affinity to gp120 depends on gp120 sequence and tertiary structure.
• For HIV-1, sCD4 binding induces gp120 dissociation from gp41, exposing cryptic gp41 epitopes and triggering fusion.
• CD4-induced molecular rearrangements in gp120 are more subtle in primary HIV-1, HIV-2, and SIV isolates.

Conclusions:

• CD4 binding is necessary and sufficient for activating HIV fusion.
• Receptor-mediated activation of fusion involves exposing fusogenic gp41 components.
• The gp120 V3 loop and gp41 N-terminus are critical for HIV entry.