Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• The gp120 V3 loop of human immunodeficiency virus type 1 (HIV-1) is known to bind polyanions, influencing virus infectivity and neutralization.
• Previous studies focused on T-cell-line-adapted, CXCR4-using HIV-1, limiting understanding of other gp120 regions' polyanion binding capabilities.

Purpose of the Study:

• To investigate potential secondary polyanion binding sites on HIV-1 gp120 beyond the V3 loop.
• To characterize the role of the coreceptor binding region in gp120-polyanion interactions.
• To explore the differential binding of polyanions to various HIV-1 gp120 tropisms (X4, R5, R5X4).

Main Methods:

• Monoclonal antibody inhibition assays.
• Labeled heparin binding experiments.
• Surface plasmon resonance (SPR) studies.
• Analysis of mutated gp120 variants.
• Molecular modeling of gp120 electrostatic potential.

Main Results:

• A second polyanion binding site was identified on gp120, likely within the conserved coreceptor binding region.
• Polyanion binding to the coreceptor site interfered with gp120-CXCR4 interaction but not gp120-CD4 interaction.
• Polyanion binding was significant for X4 and R5X4 gp120 but weak or undetectable for R5 gp120.
• The V3 loop was the primary determinant for polyanion binding, with subtle influences from other regions like V1/V2 loops and termini.

Conclusions:

• HIV-1 gp120 exhibits selective polyanion binding, involving both the V3 loop and the coreceptor binding region.
• The conserved coreceptor binding surface represents a potential novel and conserved target for therapeutic interventions against HIV-1.