Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses

Abstract

Certain human pathogens avoid elimination by our immune system by rapidly mutating the surface protein sites targeted by antibody responses, and consequently they tend to be problematic for vaccine development. The behavior described is prominent for a subset of viruses--the highly antigenically diverse viruses--which include HIV, influenza, and hepatitis C viruses. However, these viruses do harbor highly conserved exposed sites, usually associated with function, which can be targeted by broadly neutralizing antibodies. Until recently, not many such antibodies were known, but advances in the field have enabled increasing numbers to be identified. Molecular characterizations of the antibodies and, most importantly, of the sites of vulnerability that they recognize give hope for the discovery of new vaccines and drugs.

Fig 1. A model of the HIV-1 Envelope spike with select bnMAbs bound

The spike model is derived from cryo-electron tomography from (72), EM databank codes EM-5019 and EM-5021. The Fabs are color-coded in Fig 1 and Fig 2 to represent different sites of interaction on the Env proteins. The pinkish red Fabs bind to the Env stem that houses the fusion machinery, the green Fabs bind at or around the receptor binding site (CD4 receptor for HIV-1 and sialylated glycans for influenza), and the yellow Fabs bind and penetrate the glycan shield for HIV-1. Anti-HIV Fabs shown are PG9 (yellow, on top, 3u4e) (34), PGT128 (yellow at 11 o'clock, 3tyg) (33), VRC01 (green, 3ngb) (32), 4E10 (salmon at bottom left, 2fx7) (73), and 2F5 (pink at bottom right, 2f5b) (74). Carbohydrates (Man9) were modeled onto an unliganded YU2 gp120 core (3tgq) (75) with GlyProt from the glycosciences.de website, except for the glycans binding to PGT128 and PG9 that were taken directly from their structures in complex with outer domain (33) and scaffold (34), respectively. The locations of PG9, 4E10, and 2F5 are approximate; however, the VRC01 and PGT128 were docked by superposition of gp120 core or outer domain, respectively, with the unliganded YU2 gp120 model (that is invisible under the EM mesh). Figure was made with Pymol (76).

Fig 2. A model of the influenza virus spike with select bnMAbs bound

EM-5021 membrane density was used to approximate the membrane surface. Anti-influenza virus Fabs are 2D1 (top, light green, 3lzf) (77), CH65 (top, dark green, 3sm5) (47), FI6 (bottom right, link pink, 3ztj) (43), CR6261 (bottom center, salmon, 3gbm) (40), and CR8020, (bottom, left, red, 3sdy) (42). HA is the 1918 strain (pdb 3r2x) (55), with Man₉ carbohydrates modeled on with GlyProt (78) to give approximate dimensions for the attached glycans.