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Publication Abstract from PubMed

The conserved HIV-1 site of co-receptor binding is protected from antibody-directed neutralization by conformational and steric restrictions. While inaccessible to most human antibodies, the co-receptor site has been shown to be accessed by antibody fragments. Here, we use X-ray crystallography, surface plasmon resonance, and pseudovirus neutralization to characterize the gp120-envelope glycoprotein recognition and HIV-1 neutralization of a heavy chain-only llama antibody, named JM4. We describe full-length IgG2b- and IgG3-llama versions of JM4 that target the co-receptor-binding site and potently neutralize over 95% of circulating HIV-1 isolates. Contrary to established trends that show improved access to the co-receptor-binding region by smaller antibody fragments, the single-domain (VHH) version of JM4 neutralized less well than the full length-IgG2b version of JM4. The crystal structure at 2.1 A resolution of JM4-VHH bound to HIV-1 YU2 gp120 stabilized in the CD4-bound state by the CD4-mimetic miniprotein, M48U1, revealed a JM4 epitope that combined regions of co-receptor recognition (including the gp120 bridging sheet, V3 loop and beta19 strand) with gp120-structural elements involved in recognition of CD4 such as the CD4-binding loop. The structure of JM4 with gp120 thus defines a novel CD4-induced site of vulnerability involving elements of both co-receptor- and CD4-binding sites. The potently neutralizing JM4-IgG2b antibody that targets this newly defined site of vulnerability adds to the expanding repertoire of broadly neutralizing antibodies that effectively neutralize HIV-1, and thereby potentially provides a new template for vaccine development and target for HIV-1 therapy.

Heavy chain-only IgG2b-llama antibody effects near-pan HIV-1 neutralization by recognizing a CD4-induced epitope that includes elements of both CD4- and co-receptor-binding sites.,Acharya P, Luongo T, Georgiev I, Matz J, Schmidt SD, Louder MK, Kessler P, Yang Y, McKee K, O'Dell S, Chen L, Baty D, Chames P, Martin L, Mascola JR, Kwong PD J Virol. 2013 Jul 10. PMID:23843638^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.