Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• The HIV-1 envelope (Env) trimer spike is a key target for vaccines designed to elicit broadly neutralizing antibodies (bNAbs).
• Recent advancements in bNAb isolation, soluble trimer mimics, and binding assay techniques enable detailed antigenic structure analysis.
• Understanding Env trimer antigenicity is crucial for developing effective HIV-1 vaccines and therapies.

Purpose of the Study:

• To create a comprehensive antigenic map of the HIV-1 Env trimer using antibody cross-competition assays.
• To delineate epitope clusters and understand interrelationships between antibody binding sites.
• To identify novel mechanisms of antibody cross-competition on the Env trimer.

Main Methods:

• Utilized antibody cross-competition assays with a soluble Env trimer mimic (BG505 SOSIP.664 gp140).
• Employed oriented immobilization of tagged trimers for facile binding assays.
• Analyzed epitope clusters including the CD4 binding site, V1V2, and Asn332-glycan patch, as well as the gp120-gp41 interface.

Main Results:

• Delineated three major epitope clusters: CD4 binding site, quaternary V1V2, and Asn332-centered oligomannose patch.
• Identified new epitopes at the gp120-gp41 interface and characterized relationships among clusters.
• Defined three cross-competition mechanisms: steric, allosteric inhibition, and glycan reorientation, demonstrating complex bNAb binding.

Conclusions:

• The antigenic map reveals intricate epitope relationships and complex antibody binding dynamics on the Env trimer.
• Findings provide critical insights into the structural basis of broadly neutralizing antibody recognition.
• This knowledge will guide the rational design of HIV-1 vaccines and bNAb-based therapeutics.