Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

Abstract

Respiratory syncytial virus (RSV) infection is a significant cause of hospitalization of children in North America and one of the leading causes of death of infants less than 1 year of age worldwide, second only to malaria. Despite its global impact on human health, there are relatively few therapeutic options available to prevent or treat RSV infection. Paradoxically, there is a very large volume of information that is constantly being refined on RSV replication, the mechanisms of RSV-induced pathology, and community transmission. Compounding the burden of acute RSV infections is the exacerbation of preexisting chronic airway diseases and the chronic sequelae of RSV infection. A mechanistic link is even starting to emerge between asthma and those who suffer severe RSV infection early in childhood. In this article, we discuss developments in the understanding of RSV replication, pathogenesis, diagnostics, and therapeutics. We attempt to reconcile the large body of information on RSV and why after many clinical trials there is still no efficacious RSV vaccine and few therapeutics.

Keywords: diagnostics; epidemiology; experimental therapeutics; immunization; respiratory syncytial virus; viral pathogenesis.

FIG 1

Binding and entry of RSV into the host cell. Candidate receptors of RSV (A) such as TLR4, CX3CR1, and HSPG (B) bind to the RSV-G glycoprotein and act to tether the virus particle to the cell surface. Cell surface nucleolin may also be involved in the entry process (C) by triggering fusion of the virus and host cell membranes by binding to the RSV-F fusion glycoprotein (D). The virion fuses with the cell membrane and enters the cell, one of the last events of virus entry that must take place for successful replication of RSV in the host cell (E). Host cell macropinocytosis of RSV is also a route of entry for RSV (F). It is unclear which receptors are involved in this process (G). Internalization of the virion (H) is dependent on actin rearrangement, phosphatidylinositol 3-kinase activity, and host cell (I) early endosomal Rab5⁺ vesicles where proteolytic cleavage of the RSV-F protein triggers delivery of the capsid contents into the host cells by fusion of the virus and endosomal membranes (J).

FIG 2

Fusion process between the RSV envelope and cellular membrane. The RSV envelope has multiple protruding RSV-F fusion glycoproteins, anchored via transmembrane domains (A). In the prefusion state, RSV-F exists as a spring-loaded trimer with the major neutralization epitopes shown at the N-terminal region. The major antigenic site Ø exists only on the prefusion trimer and is lost after fusion. Interaction between the RSV-F trimer and a receptor may cause RSV-F to undergo a dramatic conformational shift (B), which leads to insertion of the fusion peptide into the host cell membrane (C) and forcing of the viral and host membranes into close contact (D). Although only two RSV-F monomers are depicted for simplicity, the combined force of multiple RSV-F conformational shifts is required to overcome the thermodynamic barrier of mixing membranes and establish a stable fusion pore for viral nucleocapsid delivery (E).

FIG 3

Inclusion bodies and stress granule formation in RSV-infected host cells. Host cell protein kinase R (PKR) detects double-stranded RNA, a by-product of viral replication, and then phosphorylates the translation initiation factor eIF2α. Therefore, stress granule formation is a product of the host innate response against infection that downregulates both host and viral protein synthesis. However, viral countermeasures include preventing the phosphorylation of eIF2α via RSV-N and sequestering stress granule-promoting proteins like O-linked N-acetylglucosamine transferase within viral inclusion bodies, thereby preventing stress granule formation. The exact roles of stress granules and their relation to inclusion bodies within an RSV infection in vivo are still debatable; in addition, it will be important to determine the impact of RSV-induced cellular stress on the future development of airway diseases such as asthma.

FIG 4

Association of IL-33 with asthma during RSV infection. Based on animal models, IL-33 may be induced in the lungs of infants. IL-33 stimulates group 2 innate lymphoid cells (e.g., nuocytes) to propagate and release the asthma-promoting cytokines IL-4, IL-5, and IL-13. Sloughing of infected ciliated bronchial epithelial cells is mediated by the RSV accessory protein NS-2, which transmits infection into the lower respiratory tract. Bacterial coinfections during RSV infection are common, and prior colonization with potentially pathogenic bacterial species may be a risk factor for severe RSV infection.

FIG 5

Seasonality and positivity rate of RSV in Alberta, Canada, 2008 to 2015. The graph indicates RSV test-positive specimens and overall respiratory virus test volumes by Luminex RVP classic assay. Data show specimens that were influenza virus negative and do not account for mixed infections by RSV and other pathogens. Peak periods occur in winter and early spring, with positivity for RSV ranging from 15 to 35% of all specimens tested by RVP.