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Review
. 2019 Nov 29:10:2778.
doi: 10.3389/fimmu.2019.02778. eCollection 2019.

Antibody Epitopes of Pneumovirus Fusion Proteins

Jiachen Huang  1   2 , Darren Diaz  1   2 , Jarrod J Mousa  1   2
Affiliations
Review

Antibody Epitopes of Pneumovirus Fusion Proteins

Jiachen Huang et al. Front Immunol. .

Abstract

The pneumoviruses respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two widespread human pathogens that can cause severe disease in the young, the elderly, and the immunocompromised. Despite the discovery of RSV over 60 years ago, and hMPV nearly 20 years ago, there are no approved vaccines for either virus. Antibody-mediated immunity is critical for protection from RSV and hMPV, and, until recently, knowledge of the antibody epitopes on the surface glycoproteins of RSV and hMPV was very limited. However, recent breakthroughs in the recombinant expression and stabilization of pneumovirus fusion proteins have facilitated in-depth characterization of antibody responses and structural epitopes, and have provided an enormous diversity of new monoclonal antibody candidates for therapeutic development. These new data have primarily focused on the RSV F protein, and have led to a wealth of new vaccine candidates in preclinical and clinical trials. In contrast, the major structural antibody epitopes remain unclear for the hMPV F protein. Overall, this review will cover recent advances in characterizing the antigenic sites on the RSV and hMPV F proteins.

Keywords: RSV; X-ray crystallography; antibody—antigen complex; hMPV; human metapneumovirus; pneumovirus infections; respiratory syncytial virus.

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Figures

Figure 1
Figure 1
X-ray crystal structures of pneumovirus F proteins alone and in complex monoclonal antibody fragments. (A) The main antigenic sites on the RSV F protein are depicted on a monomer of the F protein (PDB ID: 5C6B). (B) The same structure as in (A) is colored according to sequence conservation with hMPV F. Conserved residues are shown in maroon, and primarily reside within antigenic sites III, IV, and V. Sequences of RSV and hMPV F were derived from PDB IDs: 5C6B and 5WB0. (C) The pre-fusion specific antibody D25 binds at the apex of pre-fusion RSV F (PDB ID: 4JHW). (D) hRSV90 binds antigenic site V and is pre-fusion-specific (PDB ID: 5TPN). (E) MPE8 is pre-fusion-specific and cross-reactive with hMPV F (PDB ID: 5U68). (F) 14N4 is a human antibody that targets antigenic site II and binds both pre-fusion and post-fusion RSV F (PDB ID: 5J3D). (G) The humanized mouse mAb, 101F, binds at antigenic site IV. For this structure, the crystal structure of 101F binding the site IV peptide (PDB ID: 3O41) was aligned with antigenic site IV of the post-fusion RSV F protein (3RRR). (H) The non-neutralizing site I mAb ADI14359 was isolated from an RSV-infected infant, and is preferential for post-fusion RSV F (PDB ID: 6APB). (I) DS7 is a hMPV F-specific mAb that was co-crystallized with a fragment of pre-fusion hMPV F. The structure of the DS7-F complex (PDB ID: 4DAG) is overlaid onto the trimeric pre-fusion hMPV F structure (PDB ID: 5WB0). All antibodies are colored in accordance with the text label, the RSV F protein is shown in cyan, and the hMPV F protein is shown in wheat. All figures and alignments were prepared in PyMol and Chimera.
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