A Broadly Neutralizing Antibody Targets the Dynamic HIV Envelope Trimer Apex via a Long, Rigidified, and Anionic...

Area of Science:

• Immunology and Virology
• Structural Biology

Background:

• Broadly neutralizing antibodies (bnAbs) are crucial for HIV vaccine development, acting as prophylactic and therapeutic agents.
• Potent bnAbs often target a quaternary epitope at the apex of the surface HIV envelope (Env) trimer, a key vaccine target.

Purpose of the Study:

• To determine the atomic structure of an apex bnAb, PGT145, in complex with the HIV Env trimer.
• To elucidate the molecular mechanism by which PGT145 recognizes and binds the Env trimer.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to solve the high-resolution structure of the PGT145-Env complex.
• Structural analysis focused on the interaction between the antibody's HCDR3 loop and the Env trimer surface.

Main Results:

• The long, anionic HCDR3 of PGT145 was observed to penetrate between glycans at the Env trimer's 3-fold axis.
• PGT145 directly contacted peptide residues from all three Env protomers, explaining its high trimer specificity.
• Somatic hypermutation in other complementarity-determining regions (CDRs) stabilized the HCDR3, enabling recognition of conserved basic residues involved in Env trimer disassembly.

Conclusions:

• The study reveals a unique binding mode for PGT145, highlighting the immune system's ability to evolve sophisticated recognition strategies.
• Understanding this interaction provides insights into HIV entry mechanisms and informs the design of novel HIV immunogens and therapeutics.