title: Heavy chain-only IgG2b llama antibody effects near-pan HIV-1 neutralization by recognizing a CD4-induced epitope that includes elements of coreceptor- and CD4-binding sites.
abstract: The conserved HIV-1 site of coreceptor binding is protected from antibody-directed neutralization by conformational and steric restrictions. While inaccessible to most human antibodies, the coreceptor site has been shown to be accessed by antibody fragments. In this study, we used 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 versions of JM4 that target the coreceptor-binding site and potently neutralize over 95% of circulating HIV-1 isolates. Contrary to established trends that show improved access to the coreceptor-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-Å resolution of VHH JM4 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 coreceptor recognition (including the gp120 bridging sheet, V3 loop, and β19 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 coreceptor- 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.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. acharyap@mail.nih.gov
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Luongo
authors.forename: Ivelin S
authors.initials: IS
authors.lastname: Georgiev
authors.forename: Julie
authors.initials: J
authors.lastname: Matz
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Schmidt
authors.forename: Mark K
authors.initials: MK
authors.lastname: Louder
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Krisha
authors.initials: K
authors.lastname: McKee
authors.forename: Sijy
authors.initials: S
authors.lastname: O'Dell
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Daniel
authors.initials: D
authors.lastname: Baty
authors.forename: Patrick
authors.initials: P
authors.lastname: Chames
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.forename: John R
authors.initials: JR
authors.lastname: Mascola
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry / Q000276:immunology*; D001665:Binding Sites / Q000276:immunology; D002161:Camelids, New World; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000737:chemistry / Q000276:immunology*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000276:immunology*; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology*; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology*; D009500:Neutralization Tests; D020349:Surface Plasmon Resonance
chemical_list: D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007074:Immunoglobulin G; C514793:gp120 protein, Human immunodeficiency virus 1