Structural Basis for Epitopes in the gp120 Cluster A Region that Invokes Potent Effector Cell Activity

Abstract

While a number of therapeutic options to control the progression of human immunodeficiency virus (HIV-1) now exist, a broadly effective preventive vaccine is still not available. Through detailed structural analysis of antibodies able to induce potent effector cell activity, a number of Env epitopes have been identified which have the potential to be considered vaccine candidates. These antibodies mainly target the gp120 Cluster A region which is only exposed upon viral binding to the target cell with epitopes becoming available for antibody binding during viral entry and fusion and, therefore, after the effective window for neutralizing antibody activity. This review will discuss recent advances in the structural characterization of these important targets with a special focus on epitopes that are involved in Fc-mediated effector function without direct viral neutralizing activities.

Keywords: A32; ADCC; C11; HIV; structure; vaccine.

Figure 1

Cluster A antibodies in complex with gp120 antigens. (A) Structures shown are of: N5-i5Fab-gp120_93TH057core_e-d1d2CD4 (PDB code: 4H8W), N60-i3Fab-gp120_93TH057core_e-M48U1 (4RFO), 2.2cFab-gp120_YU2core_e-M48U1 (4R4F), A32Fab-gp120_93TH057-ID2 (4YC2), N12-i3Fab-gp120_93TH057core_e+N/C-M48U1 (5W4L), and JR4Fab-gp120_93TH057core_e-M48 (4RFN). For each complex only the gp120 and Fab molecules are shown as ribbon diagrams. Images were generated with Pymol (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC, San Carlos, CA, USA). (B) The binding footprint of each antibody highlighted in black. Colored text corresponds to the areas depicted in A; pink: seven-/eight-stranded β-sandwich, yellow: gp120 mobile layer 1, light blue: mobile layer 2, beige: layer 3, and grey: the gp120 outer domain. gp120 secondary structure elements are depicted above the sequence as arrows for β-strands and cylinders for α-helices.

Figure 2

HIV-1 Epitopes. (A) Structure of a native, un-triggered virion-associated HIV-1 trimer showing the location of nascent C11 region and A32 region epitopes enclosed in the center of the non-CD4 bound trimer. (B) Structure of the HIV-1 trimer in the CD4 receptor bound confirmation. Binding exposes the C11, A32, and A32–C11 mixed epitope regions. The binding sites of all antibodies discussed in this review are depicted. Images were generated with Pymol (The PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC, San Carlos, CA, USA).