Respiratory Syncytial Virus (RSV) is a common cause of respiratory infections, particularly affecting infants, young children, and older adults worldwide. This virus is a leading cause of lower respiratory tract infections in children under five years old. Understanding the intricate structure of RSV is fundamental to comprehending how it operates and to developing effective methods for prevention and treatment.
Overall Architecture of the Virus
The Respiratory Syncytial Virus (RSV) virion is typically spherical or pleomorphic, around 130 nanometers in diameter, though some can form elongated filamentous structures, extending several hundred nanometers to over 10 micrometers in length. It is an enveloped virus, possessing an outer lipid membrane derived from the host cell during its release. Embedded within this viral envelope are surface glycoproteins, appearing as short spikes. Beneath the envelope lies the matrix protein layer, encasing the internal ribonucleoprotein (RNP) complex.
The internal RNP complex contains the viral RNA genome, tightly associated with nucleocapsid proteins, forming a helical structure protected within the viral particle. These elements, along with the matrix layer and surface glycoproteins, form the complete viral particle, enabling the virus to attach to and infect host cells.
Key Structural Components and Their Functions
The RSV virion comprises several distinct proteins, each with specialized roles in the viral life cycle. The Fusion (F) protein is a transmembrane glycoprotein that mediates the virus’s entry into host cells by fusing the viral and host cell membranes. It exists in two primary conformations: a metastable prefusion state and a stable postfusion state, with the prefusion form being particularly important for eliciting neutralizing antibodies. This protein is synthesized as an inactive precursor (F0) which is then cleaved into F1 and F2 subunits, linked by disulfide bonds, to become active.
The Glycoprotein (G) is the primary attachment protein, binding the virus to host cell surfaces. It interacts with specific receptors on host cells. While its main function is attachment, the G protein also contributes to immune evasion by modulating the host immune response.
The Small Hydrophobic (SH) protein is a small transmembrane protein whose function is less understood compared to F and G proteins. Research suggests it may play a role in virus morphogenesis, pathogenicity, and enhancing host membrane permeability. It has also been shown to inhibit tumor necrosis factor alpha (TNF-α) signaling, potentially delaying host inflammatory responses.
The Matrix (M) protein is located beneath the viral envelope. This protein plays a role in viral assembly and budding, coordinating the formation of new virions at the plasma membrane. The M protein forms dimers and can transition into higher-order oligomers, which triggers viral filament assembly and virus production.
The Nucleoprotein (N) encapsidates the single-stranded negative-sense RNA genome, forming a helical nucleocapsid. This N-RNA complex serves as the template for viral transcription and replication. The N protein protects the viral RNA from degradation and recognition by host immune receptors.
The Phosphoprotein (P) and Large (L) protein are components of the viral RNA polymerase complex. The P protein acts as a cofactor for the L protein, linking it to the nucleocapsid complex. The L protein is the RNA-dependent RNA polymerase, responsible for transcribing viral messenger RNAs (mRNAs) and replicating the viral genome. It contains enzymatic domains for nucleotide polymerization, cap addition, and methyltransferase activities.
The viral RNA genome is a non-segmented, single-stranded negative-sense RNA molecule. It contains 10 open reading frames that encode 11 structural and non-structural proteins, each contributing to the virus’s life cycle.
How Structure Drives Infection
The infection process of RSV begins with the attachment of the virus to host cells, primarily ciliated epithelial cells in the respiratory tract. This attachment is largely mediated by the Glycoprotein (G), which binds to specific receptors on the host cell surface. The G protein’s interaction with host cell receptors, such as heparan sulfate proteoglycans and CX3CR1, initiates the binding process.
Following attachment, the Fusion (F) protein becomes active, mediating the entry of the virus into the host cell. The F protein facilitates the fusion of the viral envelope with the host cell’s plasma membrane, allowing the internal contents of the virus, including its ribonucleoprotein complex, to enter the cytoplasm. This fusion event is a conformational change in the F protein from its prefusion to its postfusion state.
Once inside the host cell, the viral RNA genome, encapsidated by the Nucleoprotein (N), is released into the cytoplasm. The viral RNA-dependent RNA polymerase complex, composed of the Large (L) protein and the Phosphoprotein (P), then begins the processes of transcription and replication. The L protein synthesizes viral mRNAs from the negative-sense RNA genome, which are then translated into viral proteins by the host cell machinery. The polymerase also replicates the viral genome by first creating a positive-sense antigenome, which then serves as a template for new negative-sense RNA genomes.
As viral proteins and new genomes are produced, the Matrix (M) protein coordinates the assembly of new virions. The M protein interacts with the cytoplasmic tails of the surface glycoproteins and the ribonucleoprotein complex, directing their localization to specific areas of the host cell membrane. New virions then bud out from the host cell surface, acquiring their lipid envelope and surface glycoproteins during this release process. This continuous cycle of attachment, entry, replication, assembly, and budding drives the spread of RSV infection within the host.
Leveraging Structure for Medical Advances
Understanding the detailed structure of RSV has advanced the development of strategies for preventing and treating infections. The Fusion (F) protein, particularly its prefusion conformation, has emerged as a target for vaccine development. Researchers discovered that antibodies targeting the prefusion F protein are more effective at neutralizing the virus compared to those targeting the postfusion form. This insight led to the stabilization of the prefusion F protein, making it a more effective vaccine antigen.
Several RSV vaccines currently approved or in advanced clinical trials utilize this stabilized prefusion F protein to induce strong neutralizing antibody responses. These vaccines aim to teach the immune system to recognize the prefusion F protein, blocking viral entry and infection. This structural understanding has accelerated vaccine development, leading to approved vaccines for older adults and pregnant individuals.
Beyond vaccines, the RSV F protein is also a target for antiviral drugs. Small molecule inhibitors have been developed that bind to specific sites on the F protein, preventing conformational changes necessary for membrane fusion and viral entry. Other antiviral strategies focus on inhibiting the viral RNA polymerase complex, disrupting the virus’s ability to replicate its genome and transcribe its genes.
Monoclonal antibodies also represent a successful passive immunization strategy, leveraging the knowledge of RSV surface proteins. Palivizumab, a monoclonal antibody, binds to a conserved site on the F protein, preventing viral entry and spread. Newer monoclonal antibodies, such as nirsevimab, target the F protein with enhanced efficacy, offering protection for infants and young children during their first RSV season. These advancements underscore how structural biology informs the design of countermeasures against RSV.