Respiratory syncytial virus entry and how to block it

Abstract

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. Although the virus was isolated in 1955, an effective RSV vaccine has not been developed, and the only licensed intervention is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody. During the past 5 years, however, there has been substantial progress in our understanding of the structure and function of the RSV glycoproteins and their interactions with host cell factors that mediate entry. This period has coincided with renewed interest in developing effective interventions, including the isolation of potent monoclonal antibodies and small molecules and the design of novel vaccine candidates. In this Review, we summarize the recent findings that have begun to elucidate RSV entry mechanisms, describe progress on the development of new interventions and conclude with a perspective on gaps in our knowledge that require further investigation.

Fig. 1. Respiratory syncytial virus virion.

a | The filamentous morphology of the virion is shown. The attachment (G) and fusion (F) glycoproteins are embedded in the viral membrane, as is the small hydrophobic (SH) protein, which functions as a viroporin. A layer of matrix (M) protein lies underneath the viral membrane and gives the virion its filamentous shape. The M2-1 protein — a transcription processivity factor — interacts with both M protein and the nucleoprotein (N) encasing the viral RNA genome. The large polymerase subunit (L) and the phosphoprotein polymerase cofactor (P) are also associated with N. b | The respiratory syncytial virus (RSV) genome shown approximately to scale for the A2 strain. The genome contains 10 genes encoding 11 proteins, with the M2 gene encoding the M2-1 and M2-2 proteins. The most highly transcribed genes are those encoding nonstructural protein 1 (NS1) and NS2, which inhibit apoptosis and interferon responses. ssRNA, single-stranded RNA.

Fig. 2. Attachment protein structure.

a | Full-length respiratory syncytial virus (RSV) attachment (G) protein domains and post-translational modifications. b | Schematic of the two RSV G isoforms. Several O-linked glycans are represented by chains of green hexagons. c | Superposition of the cystine noose and flanking regions derived from four crystal structures of RSV G-derived peptides in complex with different antigen-binding fragments (Fabs). The peptide is coloured following the spectrum from blue (amino terminus) to red (carboxyl terminus). The two disulfide bonds in the cystine noose are shown as sticks linking the helices.

Fig. 3. Fusion protein structure.

a | Schematic of fusion (F) glycoprotein maturation. F is initially synthesized as an inactive monomer containing peptide 27 (pep27). To adopt the functional prefusion conformation, pep27 must be removed by proteolysis owing to a furin-like protease, and the monomers must associate into the compact trimer. The order of events has not been definitively determined, although data favour furin processing before trimerization. b | Prefusion and postfusion trimers. Two protomers are shown as molecular surfaces coloured grey and white, whereas the third protomer is shown as a ribbon with the F₂ subunit coloured blue, F₁ coloured green, and the fusion peptide (FP) at the amino terminus of F₁ coloured red. c | Prefusion and postfusion protomers shown as ribbons. Secondary structure elements that are in different conformations or positions between the two states are coloured. Parts b and c are adapted with permission from ref., Elsevier.

Fig. 4. Attachment and fusion.

The fusion (F) protein can interact with one or more attachment factors to bind the virus to the host cell, a process that is greatly enhanced by the viral attachment protein (not shown). The F protein may also interact with a functional receptor that induces refolding of the prefusion conformation to the prehairpin intermediate. Alternatively, or in addition, the F protein spontaneously refolds at a basal rate.

Fig. 5. Fusion protein binding sites for antibodies and small molecules.

a | Location of the major antigenic sites on the prefusion and postfusion conformations of the respiratory syncytial virus (RSV) fusion (F) protein as defined in ref.. Modelled complex-type N-linked glycans are shown as sticks. b | Escape mutations of the fusion inhibitors map to three distinct regions of the RSV F protein primary amino acid sequence, coloured red, green and blue. The positions of the escape mutations are shown as coloured spheres on ribbon diagrams of the prefusion (left) and postfusion (right) conformations. c | Schematic representation of the prefusion (left) and prehairpin intermediate (right) conformations depicting the location of the fusion peptides (cylinders) and fusion-inhibitor binding site (red oval). Small-molecule fusion inhibitors bind inside the central cavity of the prefusion F conformation and interact with the fusion peptides, preventing their release and insertion into host cell membranes. Part a is adapted with permission from ref., Elsevier.