Respiratory Syncytial Virus (RSV)
Enveloped negative-sense ssRNA virus with a ~15.2 kb non-segmented genome encoding 11 proteins in 10 genes. The fusion (F) glycoprotein drives syncytium formation and is the primary neutralisation target — but only the metastable prefusion conformation exposes the highest-potency site Ø epitope. NS1 and NS2 together delay the host IFN-α/β response by 24–48 h, establishing the viral replication window. The G protein CX3C fractalkine mimic depletes CX3CR1+ memory CD8+ T cells, ensuring incomplete immunological memory and lifelong susceptibility to reinfection across all ages.
Classification & Structure
| Family / genus | Pneumoviridae / Orthopneumovirus (reclassified from Paramyxoviridae 2016); two subgroups RSV-A and RSV-B with ~50% G protein amino acid divergence; both co-circulate annually; RSV-A generally associated with slightly more severe disease |
| Genome | ~15.2 kb non-segmented negative-sense ssRNA; gene order 3'-NS1-NS2-N-P-M-SH-G-F-M2-L-5'; 10 genes encoding 11 proteins (M2 encodes M2-1 and M2-2 from overlapping ORFs) |
| F protein (Fusion) | Class I fusion homotrimer of F1/F2 disulfide-linked heterodimers; synthesised as F0 precursor, cleaved by furin at two sites; undergoes irreversible prefusion → postfusion conformational change on activation; primary neutralisation, vaccine, and mAb target |
| Prefusion vs postfusion F | Prefusion F (prefF): metastable trimer exposing site Ø (apex, highest-potency epitope, absent from postfusion) + sites II and IV; stabilised by engineered disulfide bonds (DS-Cav1 mutations: S155C/S290C/S190F/V207L). Postfusion F: stable 6-helix bundle; exposes only sites II and IV; basis for older, lower-efficacy vaccines |
| G protein (Attachment) | Heavily O-glycosylated mucin-like; binds heparan sulfate proteoglycans + CX3CR1 (fractalkine receptor); contains conserved CX3C motif — fractalkine structural mimic; shed as soluble decoy antibody sponge; ~50% amino acid divergence RSV-A vs RSV-B |
| NS1 / NS2 | Non-structural IFN antagonists encoded by genome 3' end: NS1 binds TRIM25/HERC2 ubiquitin ligases, impairs RIG-I K63-ubiquitination, promotes STAT2 proteasomal degradation; NS2 degrades IRF3 via Elongin C-Cullin E3 ligase. Together delay IFN-β production by 24–48 h post-infection |
| SH protein | Small hydrophobic viroporin; forms ion channels; blocks TNF-α-induced NF-κB signalling, dampening proinflammatory amplification loop in infected epithelium |
| L / M2-1 | L (Large RdRp): RNA-dependent RNA polymerase + 5' cap methyltransferase; target of ribavirin; M2-1: transcriptional processivity factor required for reading through gene junctions; both localise to cytoplasmic inclusion bodies (IBs) with N-RNA and P |
Infection Mechanism
1 · Attachment and membrane fusion
G protein binds heparan sulfate proteoglycans (HSPGs) on the apical surface of ciliated airway epithelial cells and type II alveolar pneumocytes, and CX3CR1 on dendritic cells and NK cells. F protein then remodels from its metastable prefusion conformation: the hydrophobic fusion peptide inserts into the target cell membrane, heptad repeat (HR1/HR2) collapse forms the six-helix bundle, and membrane merger delivers the viral RNP into the cytoplasm. The RSV F protein can fuse pH-independently — no endosomal acidification required.
2 · Transcription and replication in inclusion bodies
The RNP complex (N-RNA + P + L polymerase + M2-1 processivity factor) transcribes each genome gene sequentially from the 3' promoter, producing a gradient of mRNAs decreasing from NS1 to L (10:1 abundance ratio). Replication and transcription occur within cytoplasmic inclusion bodies (IBs) — liquid-liquid phase-separated condensates formed by N, P, M2-1, and L that concentrate the replication machinery and shield dsRNA intermediates from cytosolic MDA5/RIG-I detection. New virions bud from the apical surface of polarised epithelial cells via M protein-driven assembly.
3 · Syncytium formation and infant bronchiolitis
F protein expressed on infected cell surfaces drives fusion with adjacent uninfected cells → multinucleated syncytia (hence "syncytial" in RSV's name). In infant airways, syncytia, epithelial necrosis, mucus, and inflammatory cell debris form intraluminal plugs. Peribronchiolar lymphocytic infiltration causes submucosal oedema. Plug formation → air trapping (check-valve obstruction) → hyperinflation + atelectasis. V/Q mismatch → hypoxaemia. Infant airway radius is small: resistance ∝ 1/r⁴ (Poiseuille) — even modest oedema produces enormous airway resistance increase, explaining the severity of bronchiolitis in infants.
4 · IFN evasion — NS1/NS2 cooperative suppression
NS1 binds and disrupts the TRIM25/HERC2 ubiquitin E3 ligase complex, impairing K63-ubiquitination of RIG-I helicase; it also promotes proteasomal degradation of STAT2 via Elongin C-Cullin ubiquitin machinery. NS2 directly degrades IRF3 via its own Elongin C-Cullin interaction, preventing IFN-β promoter activation. Together they establish a 24–48 h window of impaired innate immunity during which RSV achieves high viral burdens before the antiviral state is established. SH viroporin additionally blocks TNF-α-induced NF-κB signalling to dampen the proinflammatory amplification loop.
5 · G protein CX3C motif — T cell memory impairment
The G protein contains a conserved CX3C tetrapeptide motif mimicking the chemokine fractalkine (CX3CL1). This motif binds CX3CR1 expressed on CX3CR1+ memory CD8+ T cells, NK cells, and monocytes — impairing their migration to infection sites and their antiviral effector function. The consequence is severely impaired formation of RSV-specific long-lived T cell memory. Combined with short-lived antibody responses and the modest cross-reactivity between RSV-A and RSV-B G proteins, this explains why RSV reinfection occurs throughout life regardless of how many prior infections an individual has experienced.
Host Immune Response
Disease Spectrum
| Syndrome | Age Group | Key Features |
|---|---|---|
| Bronchiolitis | Infants <12 months | Wheeze, tachypnoea, intercostal/subcostal retractions, hypoxia, feeding difficulty; RSV causes 60–75% of all bronchiolitis; leading cause of infant hospitalisation in the USA (~58,000/year) and globally (3.6 million/year) |
| Croup | 1–5 years | Barking cough, inspiratory stridor, hoarseness; RSV second most common cause after parainfluenza virus; generally milder than parainfluenza croup |
| Pneumonia | All ages | Bilateral interstitial infiltrates; more severe in infants <6 months, elderly, immunocompromised; accounts for ~25% of infant pneumonia hospitalisations |
| Upper respiratory infection | Older children, adults | Rhinorrhoea, mild cough; generally self-limiting; the common presentation throughout adulthood; virtually all adults seropositive |
| COPD/asthma exacerbation | Adults with underlying disease | RSV triggers clinically significant airway exacerbations; frequently underdiagnosed and coded as non-specific LRTI or AECB |
| Severe LRTI in elderly | Adults ≥65 years | 177,000+ US adult hospitalisations/year; mortality comparable to influenza; RSV-A generally associated with slightly worse outcomes; exacerbates COPD, CHF, and renal failure |
| Disseminated / fatal RSV | HSCT, haematological malignancy | Upper RTI progresses to LRTI in 25–40%; LRTI mortality 30–90% in early post-HSCT period; ribavirin ± IVIG ± palivizumab used in high-risk settings with limited evidence base |
Treatment & Prevention
Nirsevimab (Beyfortus) — extended half-life mAb prophylaxis
Extended half-life bispecific monoclonal antibody with YTE Fc modification (t½ ~71 days); targets both site Ø and site II of the RSV prefusion F protein (active against both RSV-A and RSV-B). Single IM injection provides season-long protection. MELODY Phase III RCT: >75% efficacy against RSV-associated LRTI hospitalisation in healthy late-preterm and term infants. Recommended for all infants ≤8 months entering their first RSV season and high-risk children ≤24 months entering their second season. Has largely superseded palivizumab for most indications globally.
Palivizumab (Synagis) — prior standard; site II mAb
Humanized monoclonal antibody targeting F protein site II only (postfusion epitope); requires monthly IM injections throughout RSV season. ~55% reduction in RSV hospitalisation in high-risk infants (premature <29 weeks, CHD, CLD/BPD). Now largely superseded by nirsevimab but may still be used in select high-risk groups pending nirsevimab formulary access in some markets.
Abrysvo (Pfizer) — bivalent prefF maternal/adult vaccine
Bivalent stabilised prefusion F protein subunit vaccine (RSV-A + RSV-B prefF); no adjuvant required. Maternal immunisation (32–36 weeks gestation): >80% efficacy against infant RSV-LRTI within 6 months post-partum via transplacental antibody transfer (MATISSE trial). Adults ≥60 years: >66% efficacy against RSV-LRTI. Licensed 2023 — first RSV vaccine for pregnant women and older adults.
mRESVIA (Moderna) — mRNA vaccine for older adults
mRNA lipid nanoparticle encoding stabilised prefusion F protein; single dose; adults ≥60 years. >83% efficacy against RSV-associated LRTI in Phase III trials. Licensed 2024; the first licensed mRNA vaccine outside COVID-19. Provides an alternative to Abrysvo for adult RSV prevention.
Supportive care and ribavirin
Supportive care is the mainstay for all ages: supplemental oxygen, high-flow nasal cannula (HFNC), CPAP, nasogastric feeding in infants with poor oral intake. Bronchodilators and corticosteroids have no proven benefit in infant bronchiolitis (multiple Cochrane meta-analyses negative). Ribavirin (aerosolised or IV L polymerase inhibitor) is reserved for severe RSV in HSCT/immunocompromised patients; evidence from RCTs is limited and outcomes data conflicting.
Connections
References
- Bennett JE, Dolin R, Blaser MJ. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Elsevier; 2020. elsevier.com
- Knipe DM, Howley PM, eds. Fields Virology. 7th ed. Wolters Kluwer; 2021. lww.com
- Hammitt LL, Dagan R, Yuan Y, et al. Nirsevimab for prevention of RSV in healthy late-preterm and term infants (MELODY). N Engl J Med. 2022;386(9):837-846. doi:10.1056/NEJMoa2110275
- Kampmann B, Madhi SA, Munjal I, et al. Bivalent prefusion F vaccine in pregnancy to prevent RSV illness in infants (MATISSE). N Engl J Med. 2023;388(16):1451-1464. doi:10.1056/NEJMoa2216480
- McLellan JS, Chen M, Leung S, et al. Structure of RSV fusion glycoprotein trimer bound to a prefusion-specific neutralizing antibody. Science. 2013;340(6136):1113-1117. doi:10.1126/science.1234914
Contribute to the Pathogen Atlas
This entry covers RSV biology, inclusion body phase separation, infant bronchiolitis mechanism, and the 2023-2024 prevention revolution. Planned expansions: long-term pulmonary outcomes of infant RSV, RSV inclusion body liquid-liquid phase condensate biology, LMIC vaccine equity. Every entry follows the same schema: structured frontmatter, peer-reviewed citations, and cross-atlas links.