Structural Evolution of Glycan Recognition by a Family of Potent HIV Antibodies

• Published in: Cell Vol. 159; no. 1; pp. 69 - 79
• Main Authors: Garces, Fernando, Sok, Devin, Kong, Leopold, McBride, Ryan, Kim, Helen J., Saye-Francisco, Karen F., Julien, Jean-Philippe, Hua, Yuanzi, Cupo, Albert, Moore, John P., Paulson, James C., Ward, Andrew B., Burton, Dennis R., Wilson, Ian A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.09.2014; Elsevier
• Subjects: AIDS Vaccines - chemistry; AIDS Vaccines - immunology; Amino Acid Sequence; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - metabolism; engineering; evolution; germ cells; glycoproteins; HIV Antibodies - chemistry; HIV Antibodies - metabolism; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - immunology; HIV-1 - chemistry; HIV-1 - immunology; Human immunodeficiency virus; humans; immune system; Models, Molecular; Molecular Sequence Data; neutralizing antibodies; polysaccharides; Sequence Alignment
• DOI: 10.1016/j.cell.2014.09.009
• ISSN: 0092-8674; 1097-4172

The HIV envelope glycoprotein (Env) is densely covered with self-glycans that should help shield it from recognition by the human immune system. Here, we examine how a particularly potent family of broadly neutralizing antibodies (Abs) has evolved common and distinct structural features to counter the glycan shield and interact with both glycan and protein components of HIV Env. The inferred germline antibody already harbors potential binding pockets for a glycan and a short protein segment. Affinity maturation then leads to divergent evolutionary branches that either focus on a single glycan and protein segment (e.g., Ab PGT124) or engage multiple glycans (e.g., Abs PGT121–123). Furthermore, other surrounding glycans are avoided by selecting an appropriate initial antibody shape that prevents steric hindrance. Such molecular recognition lessons are important for engineering proteins that can recognize or accommodate glycans. [Display omitted] •Potent broadly neutralizing HIV antibody PGT124 contacts both glycan and protein•PGT124 contrasts with other family members by contacting only a single glycan•Inferred germline antibody incorporates features important for protein and glycan recognition•Antibody maturation diversifies modes of glycan recognition Structural data reveal how a family of human antibodies has evolved diverse solutions to interact with and penetrate the HIV envelope glycan defensive shield so as to potently neutralize HIV.