Flavivirus Infections in Humans


Flaviviruses are enveloped, positive‐stranded ribonucleic acid viruses that are globally emerging and cause significant human disease in the form of encephalitis or haemorrhagic fever. The medically important flaviviruses are dengue, yellow fever, Japanese encephalitis, St. Louis encephalitis, tick‐borne encephalitis (TBE) and West Nile viruses. Most flaviviruses are maintained in animal reservoirs in nature and are transmitted to humans primarily through the bite of an infected mosquito or tick. Human‐to‐human transmission can also occur through transfusion or transplantation of infected tissue. Vaccines are available for only yellow fever and Japanese and TBE; however, new vaccines for dengue and West Nile are in clinical trials in humans. Disease diagnosis can be difficult as all flaviviruses are antigenically and genetically closely related. There are no effective antiviral therapies that exist for any flavivirus so the main approach to disease control is through vaccination and vector control.

Key Concepts:

  • Flaviviruses are important global human pathogens that primarily cause encephalitis and haemorrhagic disease.

  • Flaviviruses are enveloped, positive‐stranded RNA viruses.

  • Most human flaviviral infections are asymptomatic.

  • Flaviviruses are primarily transmitted to man by the bite of an infected mosquito or tick and are maintained in nature in animal reservoirs.

  • Flaviviruses can also be transmitted between humans by transfusion or transplantation of contaminated tissue.

  • All flaviviruses are closely related so diagnosis of human disease can be difficult.

  • Most flaviviral diseases are considered emerging infections.

  • There are no effective drugs or treatments for flaviviral infections.

  • Approved human flaviviral vaccines are available for Japanese encephalitis, tick‐borne encephalitis and yellow fever.

  • Control of flavivirus outbreaks largely depend on vector‐control measures.

Keywords: virus; flavivirus; flaviviridae; encephalitic; haemorrhagic; phylogenetic; enhancement; persistent; chronic

Figure 1.

Maximum likelihood tree based on partial nonstructural (NS5) protein sequence data (see text) with the third codon position and the hypervariable loop excluded. Sequences were assumed to evolve according to the HKY85 substitution model with the rate of transitions and transversions and the extent of among‐site variation in substitution rate (γ distribution – which allows for the distribution of substitution rates) estimated from the data. Sof is a strain of FETBE virus. This tree was constructed and kindly supplied by Dr. Edward Holmes, Department of Biology, The Pennsylvania State University, Mueller Laboratory, University Park, PA 16802, USA. © Dr. Edward Holmes.

Figure 2.

Atomic structure of the flavivirus E protein in two conformations. (a) DENV2 E protein homodimer. The E protein can be subdivided into three domains: DI (red), DII (yellow) and DIII (blue). (b) TBEV E protein fusion competent homotrimer following low pH treatment. Fusion peptide shown in orange.

Figure 3.

DENV2 virion structure derived by cryoelectronmicroscopy. (a) Virion surface. (b) Arrangement of E proteins. Colour scheme is the same as Figure . Courtesy of R. Kuhn. © R. Kuhn.

Figure 4.

Organisation of the flavivirus genome and expression of proteins (genes are not drawn to scale). NCR, noncoding region; NS, nonstructural; NTPase, nucleoside triphosphatase. NS3′ and NS3″ have been identified in virus‐infected cells but, to date, have not been demonstrated to have functional helicase and/or NTPase activity.



Calisher CH, Karabatsos N, Dalrymple JM et al. (1989) Antigenic relationships among flaviviruses as determined by cross‐neutralization tests with polyclonal antisera. Journal of General Virology 70: 37–43.

Chambers TJ, Hahn CS, Galler R and Rice CM (1990) Flavivirus genome organization, expression, and replication. Annual Reviews of Microbiology 44: 649–688.

Cook S, Moureau G, Kitchen A et al. (2012) Molecular evolution of insect‐specific flaviviruses. Journal of General Virology 93: 223–234.

Kuhn RJ, Zhang W, Rossmann MG et al. (2002) Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108: 717–725.

Kuno G, Chang GJ, Tsuchiya KR, Karabatsos N and Cropp CB (1998) Phylogeny of the genus Flavivirus. Journal of Virology 72: 73–83.

Lanciotti RS, Roehrig JT, Deubel V et al. (1999) Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286: 2333–2337.

Rey FA, Heinz FX, Mandl C, Kunz C and Harrison SC (1995) The envelope glycoprotein from tick‐borne encephalitis virus at 2 Å resolution. Nature 375: 291–298.

Further Reading

Barrett AD and Higgs S (2007) Yellow fever: a disease that has yet to be conquered. Annual Review of Entomology 52: 209–229.

Barrett PN, Dorner F and Plotkin SA (1998) Tick‐borne encephalitis vaccine. In: Plotkin SA and Orenstein WA (eds) Vaccines, 3rd edn, pp. 767–780. Philadelphia: WB Saunders.

Heinz FX and Stiasny K (2012) Flaviviruses and flavivirus vaccines. Vaccine 30: 4301–4306.

Gubler DJ and Kuno G (eds) (1997) Dengue and Dengue Haemorrhagic Fever. Wallingford, UK: CAB International.

Monath TP (ed.) (1988) The Arboviruses: Ecology and Epidemiology, vols 1–5. Boca Raton, FL: CRC Press.

Monath TP (1998) Yellow fever. In: Plotkin SA and Orenstein WA (eds) Vaccines, 3rd edn, pp. 815–879. Philadelphia: WB Saunders.

Monath TP and Heinz FX (1996) Flaviviruses. In: Fields BN, Knipe BM, Howley PM et al. (eds) Fields Virology, 3rd edn, pp. 961–1034. Philadelphia: Lippincott‐Raven.

Noble CG, Chen YL, Dong H et al. (2010) Strategies for development of dengue virus inhibitors. Antiviral Research 85: 450–462.

Peters CJ (1997) Viral haemorrhagic fevers. In: Nathanson N (ed.) Viral Pathogenesis, pp. 779–799. Philadelphia: Lippincott‐Raven.

Rice CM (1996) Flaviviridae: the viruses and their replication. In: Fields BN, Knipe BM, Howley PM et al. (eds) Fields Virology, 3rd edn, pp. 931–960. Philadelphia: Lippincott‐Raven.

Rothman AL (2011) Immunity to dengue virus a tale of antigenic sin and tropical cytokine storms. Nature Reviews in Immunology 11: 532–543.

Schmitz J, Roehrig J, Barrett A and Hombach J (2011) Next generation dengue vaccines: a review of candidates in preclinical development. Vaccine 29: 7276–7284.

Simmons CP, Farrar JJ, Nguyen VV and Wills B (2012) Dengue. New England Journal of Medicine 12: 1423–1432.

Tsai TF, Chang G‐JJ and Yu YX (1998) Japanese encephalitis vaccines, In: Plotkin SA and Orenstein WA (eds) Vaccines, 3rd edn, pp. 672–710. Philadelphia: WB Saunders.

US Department of Health and Human Services (1999) Biosafety in Microbiological and Biomedical Laboratories, 4th edn. Washington, DC: US Government Printing Office.

Weaver SC (1997) Vector biology in virus pathogenesis. In: Nathanson N (ed.) Viral Pathogenesis, pp. 329–352. Philadelphia: Lippincott‐Raven.

Weaver SC and Reisen WK (2010) Present and future arboviral threats. Antiviral Research 85: 328–345.

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Roehrig, John T, and Barrett, Alan DT(Jun 2013) Flavivirus Infections in Humans. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002233.pub3]