Respiratory Syncytial Virus: Targeting the G Protein Provides a New Approach for an Old Problem

Abstract

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the United States <5 years old. In the elderly (>65 years old), RSV results in ∼175,000 hospitalizations annually in the United States with a worldwide incidence of ∼34 million. There is no approved RSV vaccine, and treatments are limited. Recently, a phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely, prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in preterm infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (MAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has reemerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human MAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This MAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab.

Keywords: F protein; G protein; RSV; monoclonal antibodies; palivizumab; respiratory syncytial virus.

FIG 1

RSV genome. (A) Ten genes produce 11 proteins. The M2-2 open reading frame (ORF) is accessed by ribosomes that reinitiate after exiting the M2-1 ORF. The G protein is produced as both membrane-bound and secreted forms via alternative translation start sites. Two antigenic subgroups (A and B) are defined by the hypervariable mucin-like regions of the G protein. (B) RSV F protein (575 amino acids [aa]) is cleaved by furin (at the arrow) to produce the F1 and F2 domains with a conformational change that promotes fusion with cell membranes; the location of heptad repeats (HR), fusion peptide, and transmembrane domain (TM) are shown. (C) The RSV G protein (298 aa) central conserved domain (CCD) includes a conformationally constrained CX3C motif (182-CWAIC-186) that is implicated in infection of lung epithelial cells through binding to CX3CR1, assisted by a heparin binding domain (HBD). The MAb TRL3D3 binds to an epitope within the CCD.