Distinct conformations of the HIV-1 V3 loop crown are targetable for broad neutralization

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• The V3 loop of HIV-1 Env protein typically induces non-neutralizing antibodies targeting the V3-crown.
• Broadly neutralizing antibodies (bnAbs) that neutralize diverse HIV-1 strains predominantly target the V3-base region.
• Most known bnAbs recognize the prefusion Env conformation.

Purpose of the Study:

• To investigate V3-crown directed broadly neutralizing Designed Ankyrin Repeat Proteins (bnDs).
• To challenge the notion that only V3-base targeting antibodies can achieve broad neutralization.
• To explore the potential of V3-crown epitopes in HIV vaccine and therapeutic strategies.

Main Methods:

• Development and characterization of V3-crown bnDs.
• Analysis of bnD binding to different HIV-1 Env conformations (prefusion vs. open).
• Structural analysis of bnD-Env interactions, focusing on conserved residues and V3 conformations.
• Analysis of antibody binding and neutralization breadth in a large HIV-1 cohort.

Main Results:

• V3-crown bnDs were developed with neutralization breadth comparable to V3-base bnAbs.
• These bnDs bind open Env conformations, distinct from the prefusion targets of most bnAbs.
• BnDs achieve breadth by targeting conserved residues accessible in two V3 conformations, including one resembling CCR5-bound V3.
• Human antibody data showed co-evolution of V3-crown reactivity and neutralization breadth.

Conclusions:

• The V3-crown region is a viable target for developing broadly neutralizing HIV-1 antibodies.
• Antibodies targeting open Env conformations, particularly V3-crown, can contribute to neutralization breadth.
• Understanding V3-crown conformational preferences is crucial for designing effective HIV preventive and therapeutic interventions.