HIV-1 R5 Macrophage-Tropic Envelope Glycoprotein Trimers Bind CD4 with High Affinity, while the CD4 Binding Site on...

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• HIV-1 R5 variants utilize CCR5 for T-cell and macrophage infection.
• Transmitted/founder viruses primarily infect T cells, while macrophage-tropic variants dominate in the brain.
• Macrophage-tropic variants possess envelope glycoproteins (Envs) adapted for low CD4 environments, but the mechanism is unclear.

Purpose of the Study:

• To investigate the CD4 binding characteristics of macrophage-tropic versus non-macrophage-tropic HIV-1 R5 Env trimers.
• To determine if CD4 binding affinity or post-binding structural rearrangements facilitate macrophage infection.

Main Methods:

• Comparative analysis of CD4-IgG binding to Env trimers from macrophage-tropic and non-macrophage-tropic R5 HIV-1 variants.
• Structural assessment of the CD4 binding site (CD4bs) accessibility on Env trimers.

Main Results:

• CD4-IgG bound efficiently to macrophage-tropic R5 Env trimers.
• Binding to non-macrophage-tropic R5 Env trimers was undetectable, indicating a highly occluded CD4bs.
• The CD4bs is occluded on Env trimers of non-macrophage-tropic R5 viruses.

Conclusions:

• HIV R5 variants infecting macrophages exhibit enhanced CD4 binding, likely due to structural adaptations in their Env trimers.
• The occlusion of the CD4bs on non-macrophage-tropic viruses may facilitate T-cell infection through viral synapses with concentrated CD4.
• Understanding these Env-CD4 interactions is crucial for developing broadly neutralizing antibodies for HIV vaccines.