Abstract
The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. Here we describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. A recombinant sublineage variant pan-neutralizes a 130-isolate panel at 1.4 μg/ml (IC50). Notably, a germline revertant with mature CDR3s neutralizes 12% of viruses and still binds MPER after DJ reversion. Crystal structures of lipid-bound PGZL1 variants and cryo-EM reconstruction of an Env-PGZL1 complex reveal how these antibodies recognize MPER and viral membrane. Discovery of common genetic and structural elements among MPER antibodies from different patients suggests that such antibodies could be elicited using carefully designed immunogens.
Highlights
The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth
MPER-positive B cells from PG13 visit 5 were sorted by fluorescence-activated cell sorting (FACS; see Methods), and the resulting heavy-chain (HC) and light-chain (LC) variable regions were cloned into IgG vectors
Antibody PGZL1 bound to full-length MPER and a 4E10specific peptide, but not to a 2F5-specific peptide (Fig. 1b)
Summary
The membrane-proximal external region (MPER) of HIV-1 envelope glycoprotein (Env) can be targeted by neutralizing antibodies of exceptional breadth. MPER antibodies usually have long, hydrophobic CDRH3s, lack activity as inferred germline precursors, are often from the minor IgG3 subclass, and some are polyreactive, such as 4E10. We describe an MPER broadly neutralizing antibody from the major IgG1 subclass, PGZL1, which shares germline V/ D-region genes with 4E10, has a shorter CDRH3, and is less polyreactive. Most bnAbs to HIV-1 have been cloned from elite donors whose plasma shows broad neutralizing activity These bnAbs target six distinct sites on the HIV-1 envelope glycoprotein (Env) spike, including the CD4-. Long heavy complementarity-determining region (CDR) H3 loops with aromatic residues at the tip facilitate bnAb binding to the hydrophobic MPER and nearby membrane[6]. 10E8 and DH511 were recently shown to recognize a similar epitope as 4E10 with less polyreactivity and higher potency[10,11], but key information is missing on the precise antigens and mechanisms that drove their evolution
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