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Penetrating the Glycan Shield on HIV‐1
Author(s) -
Kwong Peter
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.106.3
Subject(s) - glycan , epitope , antibody , trimer , immunoglobulin fab fragments , chemistry , binding site , virology , neutralizing antibody , biology , immunoglobulin light chain , glycoprotein , biochemistry , immunology , complementarity determining region , dimer , organic chemistry
The HIV‐1 envelope spike, the sole target of virus‐directed neutralizing antibodies, is covered by a dense array of N ‐linked glycans, which comprises rough half its molecular weight. Because these glycan are generated by self‐biosynthetic machinery, the human immune system can only recognize them as non‐self if they are arranged either in a unique cluster of glycans (such as the triple glycan cluster recognized by antibody 2G12) or as part of a glyco‐peptide epitope (such as observed with antibodies PG9 or 35O22). For the few surfaces on HIV‐1 that are glycan‐free, such as that recognized by the CD4 receptor, antibodies need to contend with the dense glycan that surrounds the site. Here we use crystal structures of a soluble trimeric form HIV‐1 (SOSIP.664) to investigate requirement for penetration to the nominally glycan‐free site of CD4 attachment. We analyze the crystal structure of a fully glycosylated HIV‐1 Env trimer to gain insight into the degree that surrounding N‐linked glycan sterically cover the CD4‐binding site. We also analyze crystal structures of trimeric HIV‐1 Env with antibody VRC01, a CD4‐binding‐site directed antibody capable of neutralizing ~90% of HIV‐1 isolates. The double head of a human antibody, a consequence of the heavy chain‐light chain pairing, appears to be sterically constrained relative to the single‐headed llama vHH antibodies. The vaccine implications of these findings will be discussed.