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Virus Genes

, Volume 33, Issue 2, pp 235–252 | Cite as

Respiratory syncytial virus (RSV) evades the human adaptive immune system by skewing the Th1/Th2 cytokine balance toward increased levels of Th2 cytokines and IgE, markers of allergy—a review

  • Yechiel BeckerEmail author
Original Article

Abstract

Infection of infants in their first year of life, children and elderly people with the respiratory syncytial virus (RSV) endangers the life of the patient. An attempt to develop a formalin-inactivated RSV (FI-RSV) vaccine during the 1960s resulted in an aggravated infection in immunized children, leading to hospitalization, while infection of non-immunized children produced much milder symptoms. The reason for this remained an enigma, one which was gradually solved over the last decade by many researchers who studied the molecular biology of RSV infection of respiratory ciliary cells. Clinical studies of RSV-infected patients indicated increased levels of Th2 cytokines and IgE in the patients’ sera, suggesting that an allergy-like condition developed during infection. The biomarkers of allergy caused by endogenous or environmental allergens include a marked increase of the Th2 cytokine IL-4 and IgE non-neutralizing antibodies to the allergen. The way allergens trigger allergy was deciphered recently, and will be discussed later. Studies of RSV infection led to the suggestion that RSV patients suffer from allergy prior to RSV infection, a concept that was later abandoned. Studies on HIV-1 [Y. Becker, Virus Genes 28, 319–331 (2005)] research led me to the hypothesis that since HIV-1 infection induces a marked increase of IL-4 and IgE in serum, an allergy-like condition, the AIDS stage is the result of an allergen motif that is embedded in the shed viral gp120 molecules. It is hypothesized that the viral-soluble G glycoprotein (sG) contains a T cell superantigen (Tsag) that is capable of binding to the VH3 domain of IgE/FcεRI+ hematopoietic cells, basophils, mast cells and monocytes, similar to the case of allergens, and that this aggregation causes these innate system cells to degranulate and release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13) into the blood. The way these Th2 cytokines skew the Th1/Th2 balance toward Th2 > Th1 will be discussed. The aim of the present review is to base RSV pathogenicity on the numerous very good analyses of the virus genes and to suggest a therapeutic approach to treatment that is directed at preventing the inhibitory effects of Th2 cytokines on the adaptive immune system of the patients, instead of inhibiting RSV replication by antivirals. The review of the molecular research on the role of the viral fusion (F) and attachment (G) glycoproteins of RSV provided information on their role in the virus infection: early in infection the F glycoprotein induces Th1 cells to release the Th1 cytokines IL-2, IL-12 and IFN-γ to activate precursors CTLs (pCTLs) to become anti-RSV CTLs. The G and sG glycoproteins attach to FKNR1+ ciliary respiratory epithelial cells as well as directly to eosinophils to the lungs. The sG T cell antigen can also induce the release of large amounts of Th2 cytokines from CD4+ T cells and from FCεRI+ mast cells, basophils and monocytes. By comparison to HIV-1 gp120 it is possible to show that in the G and sG proteins the T cell antigen resembles the CD4+ T cell superantigen (=allergen) domain of HIV-1 gp120 which aggregates with IgE/FCεRI+ hematopoietic cells. The increased IL-4 level in the serum inhibits the adaptive immune response: IL-4Rα+ Th1 cells stop Th1 cytokine synthesis and IL-4Rα+ B cells stop the synthesis of antiviral IgG and IgA and switch to IgE synthesis. In addition, the hematopoietic cells release histamine and prostaglandin which induce wheezing. The gradual increase of sG molecules creates a gradient of fractalkine (FKN) which directs IL-5-activated eosinophils to the lungs of the patient.

Keywords

RSV Pathogenicity genes sG glycoprotein CX3C fractalkine domain Superantigen domain Allergy Eosinophilia Bronchiolitis Cytokines and antagonists 

Notes

Acknowledgements

The author is indebted to Professor G. Darai, Hygiene Institute Karl-Ruprecht University in Heidelberg, Germany, for his suggestions and advice, and to Aviad Levine, M.Sc. for his help with the computer analyses and the graphic design of the figures and table.

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© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  1. 1.Department of Molecular Virology Faculty of MedicineThe Hebrew University of Jerusalem JerusalemIsrael

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