HIV broadly neutralizing antibody targets

Abstract

Purpose of review: To provide an update on neutralizing antibody targets in the context of the recent HIV-1 envelope trimer structure, describe new antibody isolation technologies, and discuss the implications of these data for HIV-1 prevention and therapy.

Recent findings: Recent advances in B-cell technologies have dramatically expanded the number of antibodies isolated from HIV-infected donors with broadly neutralizing plasma activity. These, together with the first high-resolution crystal and cryo-electron microscopy (cryo-EM) structures of a cleaved, prefusion HIV-1 trimer, have defined new regions susceptible to neutralization. This year, three epitopes in the gp120-gp41 interface were structurally characterized, highlighting the importance of prefusion gp41 as a target. Similar to many other broadly neutralizing antibody epitopes, these new antibodies define a target that is also highly glycan dependent. Collectively, the epitopes for broadly neutralizing antibodies now reveal a continuum of vulnerability spanning the length of the HIV-1 envelope trimer.

Summary: Progress in the last year has provided support for the use of rationally stabilized whole HIV-1 trimers as immunogens for eliciting antibodies to multiple epitopes. Furthermore, the increasing number of broad and potent antibodies with the potential for synergistic/complementary combinations opens up new avenues for preventing and treating HIV-1 infection.

FIGURE 1

The V2 site overlaps with the N332 supersite. The HIV-1 envelope (Env) trimer is shown in light (gp120) and dark (gp41) grey surface view. An expanded graphic of the V2 and N332 sites is shown in the zoomed out box. Epitopes in V2 (red), V3 (orange), or V4 (yellow) are defined as residues within 5 Å of broadly neutralizing antibodies (bNAbs) PG9, PGT122/PGT128, or PGT135, respectively. Regions of overlap between epitopes are shown with mottled colours red/orange for V2-V3, and orange/yellow for V3–V4. Key glycans are shown as spheres, labelled, and coloured according to their epitopes. Glycans predicted to be a part of the 2G12 epitope are coloured dark grey, and bordered with a dotted line. Glycans N156, N332, and N392 that are bound by bNAbs targeting different epitopes are asterisked. Proximal hypervariable regions V1 and α2 are shown in light grey. Figure based on protein databank accession code 4TVP.

FIGURE 2

The CD4bs adjoins the gp120–gp41 interface. The HIV-1 envelope trimer is shown in light (gp120) and dark (gp41) grey surface view. An expanded graphic of the CD4bs and gp120–gp41 interface sites are shown in the zoomed out box. Epitopes for VRC01 (green), 8ANC195 (purple), 35O22 (brown), or PGT151 (blue) are defined as residues within 5 Å of each respective broadly neutralizing antibody (bNAb). Key glycans are shown as spheres, labelled, and coloured according to the epitopes they comprise. Regions that make up more than one epitope are shown with mottled colours, and glycans that are bound by bNAbs targeting different epitopes are asterisked. The hypervariable region V5 is shown in light grey.

FIGURE 3

A continuum of broadly neutralizing antibody (bNAb) targets. A graphic of the HIV-1 envelope (Env) trimer is shown and surface coloured for broadly defined epitopes in V2 (red), V3 (orange), V4 (yellow), the CD4bs (green), and the gp120–gp41 interface (brown, purple, and blue for 8ANC195, 35O22, and PGT151, respectively). Overlap between these epitopes through recognition of common glycans or amino acids is indicated with mottling of the relevant colours. The highly accessible positions of hypervariable regions V1, V2, α2, V4, β 14, and V5 (coloured in cyan) are indicated with arrows. The first residue of the MPER (truncated in the HIV-1 trimer structure 4TVP) is indicated with an asterisk.