Dual conformations for the HIV-1 gp120 V3 loop in complexes with different neutralizing fabs

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• The third hypervariable (V3) loop of HIV-1 gp120 is a key determinant for viral infectivity and cell entry.
• Antibodies targeting the V3 loop can neutralize HIV-1, and understanding its structure is vital for vaccine development.
• The V3 loop interacts with chemokine receptors, influencing the types of cells infected by the virus.

Purpose of the Study:

• To determine the three-dimensional structure of the HIV-1 gp120 V3 loop in complex with neutralizing antibodies.
• To investigate the conformational flexibility of the V3 loop, particularly the conserved Gly-Pro-Gly-Arg motif.

Main Methods:

• X-ray crystallography was used to determine the structures of Fab fragments of neutralizing antibodies bound to V3 loop peptides.
• Three crystal structures were analyzed: Fab 58.2 with linear and cyclic V3 peptides from the MN isolate.

Main Results:

• The crystal structures revealed that the V3 loop peptides adopt similar conformations in both linear and cyclic forms when bound to Fab 58.2.
• A significant conformational difference was observed compared to the same peptide bound to Fab 59.1 and a similar peptide bound to Fab 50.1.
• This conformational variation is localized around the conserved Gly-Pro-Gly-Arg sequence, which is predicted to form a type II beta turn.

Conclusions:

• The HIV-1 V3 loop possesses inherent conformational flexibility, capable of adopting at least two distinct structures.
• The conserved Gly-Pro-Gly-Arg sequence at the V3 loop's tip can adopt different conformations.
• This conformational plasticity of the V3 loop may be linked to its biological functions in viral entry and infectivity.