THE RSV IMMUNE RESPONSE AND ITS ABILITY TO EVADE AND INHIBIT IFN

Salini V, Procopio AD, Ricciardi G. The RSV immune response and its ability to evade and inhibit IFN.  International Journal of Infection. 2026;10(2):54-58.

V. Salini^1*, A.D. Procopio² and G. Ricciardi³

¹ Vita-Salute San Raffaele University, Milan, Italy;
² Department of Clinical and Molecular Sciences, Università Politecnica of Marche, Ancona, Italy.
³ Orthopedics, San Severo Hospital “Masselli Mascia”, San Severo, Italy.

*Correspondence to:
Vincenzo Salini,
Vita-Salute San Raffaele University,
Milan, Italy.
e-mail: salini.vincenzo@hsr.it

Received: 30 April, 2026 Accepted: 20 July, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Respiratory syncytial virus (RSV) is an enveloped, negative-sense single-stranded RNA virus of the Pneumoviridae family that spreads through respiratory droplets and direct contact, causing respiratory tract infections. RSV pathogenesis is driven by F protein-mediated syncytium formation and airway inflammation, while diagnosis relies mainly on RT-PCR and rapid antigen tests; management is primarily supportive, with antibiotics reserved for secondary bacterial infections and monoclonal antibodies used for prevention in high-risk infants. RSV establishes recurrent infections through multiple immune evasion strategies, primarily by suppressing type I and type III interferon (IFN) responses via nonstructural protein (NS) 1 and 2, which inhibit retinoic acid-inducible gene I (RIG-I)/melanoma differentiation-associated protein 5 (MDA5) signaling, block IRF3/IRF7 activation, and promote STAT2 degradation, thereby impairing antiviral immunity. In addition, the G glycoprotein disrupts immune cell recruitment, complement activation, and antibody recognition through CX3CR1 binding, soluble G protein production, antigenic variability, and extensive glycosylation, while RSV also masks antigenic epitopes with glycans and impairs dendritic cell maturation by reducing CD80/CD86 expression and IL-12 production, collectively weakening both innate and adaptive immune responses. RSV impairs adaptive immunity by reducing IL-12 production, suppressing Th1 and promoting Th2 responses, inducing programmed cell death protein 1 (PD-1)-mediated T-cell exhaustion with diminished CD8⁺ cytotoxicity and IFN-γ production, and limiting immune memory through reduced neutralizing antibodies and G protein antigenic variability, thereby facilitating recurrent infections throughout life.

KEYWORDS: Respiratory syncytial virus, RNA virus, infection, interferon, immune evasion

INTRODUCTION

Respiratory syncytial virus (RSV) is a well-known virus capable of causing severe respiratory tract infections in individuals of all ages (1). It is a single-stranded RNA virus with negative polarity belonging to the Pneumoviridae family which primarily infects children, elderly individuals and those with weakened immune systems (2). RSV is transmitted by direct contact with infected secretions or contaminated surfaces, or through respiratory droplets.

Viral pathogenesis begins with the fusion of adjacent cells due to the F protein, resulting in the formation of syncytia and large mononuclear cells (3).  The infection causes increased mucus production, mucosal edema, epithelial cell necrosis, and inflammation (4).  In young children and infants, these phenomena can easily obstruct the bronchioles, causing bronchiolitis, difficulty breathing, apnea (especially in newborns), and pneumonia (5). RSV can also infect healthy individuals, causing cough, sore throat, runny nose, fever, and pneumonia (6). In elderly individuals or those with weakened immune systems, RSV infection can cause severe pneumonia and exacerbations of chronic respiratory diseases (6). The most common diagnostic tests include rapid antigen tests, molecular tests (RT-PCR), and in certain cases, viral culture (7). Supportive therapy can include hydration, anti-inflammatories, and oxygen therapy in severe cases (8). RSV often damages the mucous membranes where the bacteria gather, and in this case, antibiotic therapy can be helpful (9).  The use of monoclonal antibodies is a preventive measure in infants (10).

RSV IMMUNE EVASION MECHANISMS

RSV is a common etiological agent of recurrent respiratory infections that possesses numerous immune evasion mechanisms that allow it to replicate effectively in the respiratory epithelium (11). The main RSV evasion mechanism is the inhibition of the interferon (IFN) response, especially type I IFN (IFN-α and IFN-β) (12). Type III IFN (IFN-λ) is also inhibited by RSV and is particularly important in respiratory epithelial cells (13).

Nonstructural proteins (NS) 1 and 2 are important non-structural virulent proteins capable of inhibiting viral RNA recognition by the intracellular retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5) receptors. NS1 and NS2 inhibit the activation of interferon regulatory factor (IRF) 3 and 7, transcription factors required for IFN synthesis (14).  They also promote the degradation of signalling pathway proteins such as STAT2, impeding IFN signal transduction.

Impaired immune cell recruitment is caused by the G protein, which binds to the CX3CR1 chemokine receptor with its highly conserved domain (15). Immune cell deficiency results in a reduced innate immune response and modulation of the inflammatory response (16) (Table I). The G protein indirectly interferes with complement activation and produces a soluble G protein (sG), which acts as an antigenic decoy and reduces the immune response against RSV (17).  The G protein genome can present many mutations, variable regions, and strong glycosylation, resulting in reduced antibody recognition, and frequent reinfections, while the F protein is much more conserved and is the main target of vaccines and monoclonal antibodies (18).

Table I. RSV infects respiratory epithelial cells, which generates chemokines to recruit immune cells that eliminate the virus. However, an abnormal immune response causes inflammation with edema, mucus production, and obstruction of the bronchioles (bronchiolitis to RSV).

Another method of RSV evasion is due to viral glycoproteins coated with numerous sugars (19). The sugars mask antigenic epitopes to hinder antibody binding and reduce recognition by immune cells. RSV infection also extends to dendritic cells, reducing their maturation by decreasing the expression of the costimulatory molecules CD80 and CD86, thus reducing the generation of IL-12. IL-12 is a cytokine that forms a crucial bridge between the body’s immediate defences and the targeted response against viral infections (20). The release of IL-12 activates T lymphocytes, which kill infected cells and, together, form the body’s defence against RSV (21).

RSV infection induces a reduced Th1 response, inhibiting viral clearance, while promoting a Th2 response with the production of the cytokines IL-4, IL-5, and IL-13, promoting mucus production and bronchospasm (22). In severe infections, increased programmed cell death protein 1 (PD-1) expression on T lymphocytes may occur, which, by binding to its receptor PD-L1, inhibits the activation of anti-viral T lymphocytes. Infection can cause increased PD-1 expression on T lymphocytes, thereby inhibiting them, reducing the cytotoxic activity of CD8⁺ lymphocytes and the generation of IFN-γ, a cytokine that enhances cellular immunity against microorganisms, including RSV (23) (Table II). The suppression of immunity leads to a reduction in immune memory, a reduction in neutralizing antibodies, and G protein variability. These reactions make the body more vulnerable to contracting RSV multiple times throughout a lifetime (24) (Fig.1).

Table II. The inflammatory mediators, innate immune cells, and acquired immune cells which participate in RSV infection.

Fig. 1. Following respiratory syncytial virus (RSV) infection, host innate immune receptors recognize viral RNA and activate signaling pathways that induce the production of type I and type III interferons (IFNs) and pro-inflammatory cytokines, which help establish an antiviral state and promote adaptive immune responses. RSV counteracts these defenses through viral proteins, particularly nonstructural proteins (NS) 1 and 2, which interfere with pattern recognition receptor signaling, suppress IFN production, and inhibit downstream JAK-STAT signaling by targeting key signaling molecules. Together, these immune evasion mechanisms enable RSV to enhance viral replication, delay viral clearance, and contribute to prolonged infection and immunopathology.

CONCLUSIONS

RSV remains a major cause of respiratory tract infections across all age groups, particularly in infants, older adults, and immunocompromised individuals, owing to its ability to establish recurrent infections through sophisticated immune evasion mechanisms. By suppressing IFN signaling, impairing innate and adaptive immune responses, promoting T-cell exhaustion, and exploiting the antigenic variability and immunomodulatory properties of the G glycoprotein, RSV effectively escapes host immunity and limits the development of long-lasting immune protection. A better understanding of these molecular mechanisms is essential for the development of more effective vaccines, antiviral therapies, and immunoprophylactic strategies aimed at reducing the global burden of RSV disease.

Conflict of interest

The authors declare that they have no conflict of interest.

REFERENCES

1. Papi A, Ison MG, Langley JM, et al. Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults. New England Journal of Medicine. 2023;388(7):595-608. doi:10.1056/nejmoa2209604
2. Bruce EA, Stuart A, McCaffrey MW, Digard P. Role of the Rab11 pathway in negative-strand virus assembly. Biochem Soc Trans. 2012;40(6):1409-15. doi:10.1042/BST20120166
3. Li J, Ma X, Xu Z, et al. Rational design of respiratory syncytial virus dimeric F-subunit vaccines in protein and mRNA forms. eBioMedicine. 2025;119:105902. doi:10.1016/j.ebiom.2025.105902
4. Rago ARP, D’Arrigo SF, Osmani M, Espinosa CM, Torres CM. Respiratory Syncytial Virus: Epidemiology, Burden of Disease, and Clinical Update. Advances in pediatrics. 2024;71(1):107-118. doi:10.1016/j.yapd.2024.02.003
5. Moline HL, Toepfer AP, Tannis A, et al. Respiratory Syncytial Virus Disease Burden and Nirsevimab Effectiveness in Young Children From 2023-2024. JAMA Pediatrics. 2024;179(2):179-187. doi:10.1001/jamapediatrics.2024.5572
6. Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly and high-risk adults. The New England Journal of Medicine. 2005;352(17):1749-1759. doi:10.1056/NEJMoa043951
7. Ferrani S, Prazuck T, Béchet S, Lesne F, Cohen R, Levy C. Diagnostic accuracy of a rapid antigen triple test (SARS-CoV-2, respiratory syncytial virus, and influenza) using anterior nasal swabs versus multiplex RT-PCR in children in an emergency department. Infectious Diseases Now. 2023;53(7):104769-104769. doi:10.1016/j.idnow.2023.104769
8. Griffiths C, Drews SJ, Marchant DJ. Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment. Clinical Microbiology Reviews. 2016;30(1):277-319. doi:10.1128/cmr.00010-16
9. Mazur NI, Caballero MT, Nunes MC. Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies. The Lancet. 2024;404(10458):1143-1156. doi:10.1016/s0140-6736(24)01716-1
10. Mazur NI, Terstappen J, Baral R, et al. Respiratory syncytial virus prevention within reach: the vaccine and monoclonal antibody landscape. The Lancet Infectious Diseases. 2022;23(1):e2-e21. doi:10.1016/s1473-3099(22)00291-2
11. Agac A, Kolbe SM, Ludlow M, Osterhaus ADME, Meineke R, Rimmelzwaan GF. Host Responses to Respiratory Syncytial Virus Infection. Viruses. 2023;15(10):1999-1999. doi:10.3390/v15101999
12. Efstathiou C, Zhang Y, Kandwal S, Fayne D, Molloy EJ, Stevenson NJ. Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1. Frontiers in immunology. 2024;15. doi:10.3389/fimmu.2024.1395809
13. Chorvinsky E, Bhattacharya S, Bera BS, et al. Down Syndrome Alters Type III IFN and Proinflammatory Airway Epithelial Responses to Respiratory Syncytial Virus Infection. American Journal of Respiratory Cell and Molecular Biology. 2025;73(6):951-964. doi:10.1165/rcmb.2025-0068oc
14. Merritt TN, Pei J, Leung DW. Pathogenicity and virulence of human respiratory syncytial virus: Multifunctional nonstructural proteins NS1 and NS2. Virulence. 2023;15(1):2283897. doi:10.1080/21505594.2023.2283897
15. Elliott J, Lynch OT, Suessmuth Y, et al. Respiratory Syncytial Virus NS1 Protein Degrades STAT2 by Using the Elongin-Cullin E3 Ligase. Journal of virology. 2007;81(7):3428-3436. doi:10.1128/jvi.02303-06
16. Russell CD, Unger SA, Walton M, Schwarze J. The Human Immune Response to Respiratory Syncytial Virus Infection. Clinical Microbiology Reviews. 2017;30(2):481-502. doi:10.1128/cmr.00090-16
17. Anderson J, Do LAH, van Kasteren PB, Licciardi PV. The role of respiratory syncytial virus G protein in immune cell infection and pathogenesis. EBioMedicine. 2024;107. doi:10.1016/j.ebiom.2024.105318
18. Ha B, Chirkova T, Boukhvalova MS, et al. Mutation of Respiratory Syncytial Virus G Protein’s CX3C Motif Attenuates Infection in Cotton Rats and Primary Human Airway Epithelial Cells. Vaccines. 2019;7(3):69. doi:10.3390/vaccines7030069
19. Rawling J, Melero JA. The Use of Monoclonal Antibodies and Lectins to Identify Changes in Viral Glycoproteins That are Influenced by Glycosylation. Methods in Molecular Biology. 2007;379:109-125. doi:10.1007/978-1-59745-393-6_8
20. Jung HE, Kim TH, Lee HK. Contribution of Dendritic Cells in Protective Immunity against Respiratory Syncytial Virus Infection. Viruses. 2020;12(1):102. doi:10.3390/v12010102
21. Collins RA, Camon EB, Chaplin PJ, Howard CJ. Influence of IL-12 on interferon-gamma production by bovine leucocyte subsets in response to bovine respiratory syncytial virus. Vet Immunol Immunopathol. 1998;63(1-2):69-72. doi:10.1016/s0165-2427(98)00083-x
22. Khan IU, Ahmad F, Zhang S, Lu P, Wang J, Xie J, Zhu N. Respiratory syncytial virus F and G protein core fragments fused to HBsAg-binding protein (SBP) induce a Th1-dominant immune response without vaccine-enhanced disease. Int Immunol. 2019;31(4):199-209. doi:10.1093/intimm/dxy078
23. Telcian AG, Laza-Stanca V, Edwards MR, et al. RSV-Induced Bronchial Epithelial Cell PD-L1 Expression Inhibits CD8+ T Cell Nonspecific Antiviral Activity. The Journal of Infectious Diseases. 2011;203(1):85-94. doi:10.1093/infdis/jiq020
24. Tang A, Chen Z, Cox KS, et al. A potent broadly neutralizing human RSV antibody targets conserved site IV of the fusion glycoprotein. Nature Communications. 2019;10(1). doi:10.1038/s41467-019-12137-1