RSV Virus Structure: Key Components and Features

Respiratory syncytial virus (RSV) is a major cause of respiratory infections, particularly in young children and older adults. Its ability to evade immune responses and efficiently infect host cells is largely due to its structural components, which play essential roles in viral replication and pathogenesis.

Viral Classification And Family

RSV belongs to the family Pneumoviridae and is classified within the genus Orthopneumovirus. It was previously grouped under Paramyxoviridae due to similarities in genome structure and replication but was later reclassified based on molecular studies. Pneumoviridae members are enveloped, negative-sense, single-stranded RNA viruses that primarily target the respiratory tract.

RSV is divided into two major antigenic subtypes: RSV-A and RSV-B. RSV-A strains tend to cause more severe disease, while RSV-B strains are often linked to milder infections. Both subtypes co-circulate during seasonal outbreaks, contributing to the virus’s persistence. Genetic sequencing reveals continuous evolution, particularly in surface glycoproteins, which can impact transmissibility and immune recognition.

RSV shares structural and functional characteristics with human metapneumovirus (HMPV), another Pneumoviridae member. Both viruses use fusion proteins for host cell entry and syncytium formation. However, RSV has unique genomic and protein features, including differences in gene order and specific non-structural proteins that regulate replication and host interactions.

RNA Genome Organization

RSV has a single-stranded, negative-sense RNA genome approximately 15.2 kilobases long. It follows a linear, non-segmented organization and encodes 11 proteins involved in replication, transcription, and structural integrity. The genomic RNA is tightly bound by the nucleoprotein (N), forming a helical ribonucleoprotein (RNP) complex, which serves as the template for viral RNA synthesis. Because RSV has a negative-sense genome, it carries its own RNA-dependent RNA polymerase (RdRP), composed of the large (L) protein and phosphoprotein (P), to transcribe and replicate its RNA within the host cell cytoplasm.

The RSV genome follows a conserved 3′-to-5′ gene order that dictates transcriptional prioritization. It begins with the non-structural proteins NS1 and NS2, which regulate viral replication and host interactions. Next are the nucleoprotein (N), phosphoprotein (P), and matrix protein (M) genes, followed by the small hydrophobic (SH) protein, glycoproteins (G and F), and the M2 gene, which encodes M2-1 and M2-2. The genome ends with the L gene, encoding the catalytic subunit of the viral RNA polymerase. Genes near the 3′ end are transcribed more abundantly than those near the 5′ end.

RSV transcription follows a stop-start mechanism, where the polymerase initiates transcription at the 3′ leader region, pausing at gene-end (GE) signals before reinitiating at gene-start (GS) sequences. This creates a transcriptional gradient, ensuring structural and replication-associated proteins are synthesized in appropriate quantities. Additionally, RSV employs mRNA editing at the M2 gene, where polymerase slippage results in extra guanine residues, leading to differential expression of M2-1 and M2-2. M2-1 enhances transcription elongation, while M2-2 shifts the balance from transcription to genome replication.

Nucleocapsid Components

The RSV nucleocapsid provides structural support for genome encapsidation and is central to viral replication. The viral RNA is tightly bound by the nucleoprotein (N), forming a helical ribonucleoprotein (RNP) complex that protects the genome while maintaining flexibility for transcription and replication. Cryo-electron microscopy reveals that the N protein adopts a left-handed helical conformation, efficiently packaging the genome while allowing polymerase access.

The phosphoprotein (P) prevents N from binding non-specifically to cellular RNA and facilitates its recruitment to viral genomes. P also interacts with the large (L) polymerase protein, assembling the functional replication complex. Mutations disrupting the N-P interface significantly impair RSV replication, highlighting its importance.

The nucleocapsid also contributes to virion assembly and budding. The matrix protein (M) links the RNP complex to the viral envelope, ensuring genome stability until entry into a new host cell. The M2-1 protein, which associates with the nucleocapsid, prevents premature polymerase dissociation, promoting efficient transcription. The coordinated interactions between these components are critical for RSV replication.

Envelope And Glycoproteins

RSV’s envelope is a lipid bilayer derived from the host cell membrane during viral budding. It contains glycoproteins essential for viral entry and spread, including G, F, and SH proteins. The G protein facilitates host cell attachment, the F protein drives membrane fusion, and the SH protein influences viral egress and stability.

The G protein, a heavily glycosylated type II membrane protein, binds to cellular receptors such as heparan sulfate proteoglycans and CX3CR1. It exists in both membrane-bound and secreted forms, with the latter potentially acting as a decoy to interfere with receptor interactions. Unlike paramyxoviruses that rely on hemagglutinin-neuraminidase, RSV’s G protein lacks neuraminidase activity and instead uses mucin-like domains for attachment.

Once RSV binds to a host cell, the F protein mediates membrane fusion, allowing viral entry. This class I fusion protein transitions from a metastable prefusion state to a stable postfusion structure. The prefusion form is the main target for antiviral strategies. Unlike influenza’s hemagglutinin, which requires low pH activation, RSV’s F protein triggers fusion at neutral pH, enabling direct cell-to-cell spread. Fusion activity also leads to syncytium formation, where infected cells merge into multinucleated structures, facilitating viral dissemination.

Matrix Protein Functions

The matrix (M) protein plays a central role in RSV assembly and budding. Located beneath the viral envelope, it connects the nucleocapsid to glycoproteins, ensuring proper virion morphology. M condenses and organizes ribonucleoprotein (RNP) complexes within budding particles, a critical step in forming infectious virions. Structural studies show that M forms a lattice-like arrangement when interacting with the viral membrane, providing stability while allowing flexibility during assembly. Mutations disrupting M’s interactions with the nucleocapsid or glycoproteins impair virion formation, reducing infectivity.

Beyond its structural role, M regulates the RSV replication cycle by modulating transcription. Early in infection, M remains dispersed in the cytoplasm, allowing active RNA synthesis. As infection progresses, M accumulates near the plasma membrane, associating with newly formed RNP complexes, suppressing transcription, and shifting the virus toward assembly. This balance ensures efficient viral propagation. Additionally, M interacts with host cytoskeletal components, aiding viral transport to budding sites and influencing cell-to-cell spread. Its multifunctionality makes it a key factor in RSV pathogenesis and a potential target for antiviral strategies.