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Figure 3 Model of the immunopathogenesis of dengue hemorrhagic fever and shock syndrome (DHF/DSS). Antibody-dependent enhancement of secondary dengue virus (V) infection by heterologous cross-reactive subneutralizing antibody results in a high virus burden in the critical target cell, the monocyte/macrophage. Interferon y production by CD4 and CD81 memory T lymphocytes induces Fc receptor and MHC antigen expression in conjunction with macrophage activation, augmenting virus infection and antigen presentation (APC). Lysis of macrophages occurs by virus-specific cytotoxic T lymphocytes (CTL) restricted by both MHC class I and II antigens. Production of TNFa by T cells and macrophages, together with other proinflammatory cytokines, contributes to the capillary leak and hemorrhagic diathesis that are characteristic of severe dengue infection. (Based on studies reviewed in Kurane I and Ennis F (1992) Immunity and immunopathology in dengue virus infections. Seminars in Immunology 4: 121-127.)

response to dengue infection. Similar findings have been obtained with human T cells. Both dengue virus-specific CD4+CD8" and CD4 CDS' cytotoxic T cell responses capable of lysing virus-infected cells have also been demonstrated. Although many viral proteins contain CTL epitopes, NS3 in particular encodes immunodominant epitopes which can drive cross-reactive CTL responses. CD4h T lymphocytes can also be stimulated with dengue antigen to produce interferon y (lEN-y). The model which incorporates all of these findings proposes that IFN7 up-regulates Fc receptor and MHC antigen expression on activated monocytes/macrophages, increasing viral burden and antigen presentation, and leading to cytotoxic lysis by dengue-sensitized memory T cells. The multiple serotype cross-reactivities and numerous T cell epitopes demonstrated in humans supports the concept that memory responses are primed for extensive activation during secondary infections. Elevated markers of T cell activation have been shown during early dengue infection in humans, including sCD8, sCD4, sIL-2, and sTNFa receptors, and IFNy. The source of the proinflammatory cytokines and the role of the T cell responses in providing protection rather than deleterious effects during dengue pathogenesis remain important questions.

Vaccines against flaviviruses

Vaccination against flaviviruses will remain an important public health measure because it is unlikely that these viruses can be eradicated from their animal reservoirs or arthropod vectors. Vaccine for yellow fever (YF17D strain) was the first available live-attenuated vaccine for this family. Derived by serial passage of its virulent parent in cell culture and eggs, YF17D is a safe, highly effective vaccine capable of inducing long-lasting protection. Yellow fever vaccination has been proposed as part of the World Health Organization (WHO) expanded program of immunization to control recurrent epidemics in Africa.

JE, DEN and TBE are also major targets for vaccine development. For TBE, a highly purified formalin-inactivated vaccine is available, which is very effective and has few side-effects. An immunoglobulin preparation against TBE is also used in Europe for pre- and postexposure prophylaxis. Products which have been used for vaccination against JE include both inactivated and live-attenuated viruses. The Biken vaccine, which has been available since the 1960s, is an inactivated preparation purified from mouse brain. Other inactivated vaccines have been developed and used locally in Asian countries. The JE SA14-14-2 vaccine is a live-attenuated virus used extensively for human vaccination within China, but is not currently approved by the WHO.

Vaccine development for DEN has been a major priority for many years but remains problematic because high levels of neutralizing antibodies against all four serotypes are required to prevent the occurrence of DHF/DSS. The most promising candidate is a live-attenuated tetravalent vaccine developed in Thailand and currently undergoing evaluation for human use. Alternatives, such as engineered cDNA clones encoding attenuated viruses, subunit vaccines incorporating the E or NS1 proteins, recombinant vector systems and subviral particles incorporating the prM and E proteins are under investigation. T helper epitopes capable of priming antibody responses have been identified within flaviviru.s K proteins, suggesting that synthetic peptides may also have value as vaccines or vaccine adjuncts.

DNA vaccination for flaviviruses has not been widely studied but protective immunity generated by recombinant plasmids encoding the prM and E proteins has been reported. There is a definite need to further investigate the cellular and molecular requirements for induction of solid protective immunity against these viruses in order to understand to what extent these various approaches will be useful. Although only a handful of flaviviruses are now targeted for vaccine development, emergence of new ones in the future may change this situation.

See also: Antibody-dependent cellular cytotoxicity; Cell-mediated immunity; Helper T lymphocytes; Cytokines; Cytotoxic T lymphocytes; Epitopes; Fc receptors; Immunopathology; Interferon y; T lymphocytes; Viruses, immunity to.

Further reading

Bray M, Men R and Lai CJ (1996) Monkeys immunized wirh interrypic chimeric dengue viruses are protected against wild-type virus challenge. Journal of Virology 70: 4162^1166. Chen Y, Maguire T, Hileman RE et al (1997) Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature Medicine 3: 866-871. Depres P, Flammand M, Ceccaldi P-K and Deubel V (1996) Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma cells, journal of Virology 70: 1384-1389. Gubler DJ and Trent DW (1994) Emergence of epidemic dengue/dengue hemorrhagic fever as a public health problem in the Americas. Infectious Agents and Disease 2: 383-393.

Hahn CS, Dalrymple JM, Strauss JH and Ricc CM (1987) Comparison of the virulent Asibi strain of yellow fever virus with the 17D vaccine derived from it. Proceedings of the National Academy of Sciences of the USA 84: 2019-2023.

Halstead SB (1988) Pathogenesis of dengue: challenges to molecular biology. Science 239: 476-481. Halstead SB (1993) Dengue virology: fifty years of problems and progress. In: Mahy BW) and Lvov DK (eds) Concepts of Virology, from lvanovsky to the Present, pp 275-284. Switzerland: Harwood Academic. Hill AB, Lobigs M, Blanden RV, Kulkarni A and Mullbachcr A (1993) The cellular immune response to Flaviviruses. In: Thomas B (ed) Viruses and the Cellular Immune Response, pp 363-388. New York: Marcel Dekker.

Kreil TR and Eibl MM (1995) Viral infection of macro-

phages profoundly alters requirements for induction of nitric oxide synthesis. Virology 212: 174-178.

Kurane I, Rothman A, Livingston P et al (1994) Immuno-pathologic mechanisms of dengue hemorrhagic fever and dengue shock syndrome. Archives of Virology S9: 59-64.

Mandl CW, Guirakhoo F, Holzmann H, Heinz FX and Kunz C (1989) Antigenic structure of the flavivirus envelope protein at the molecular level using tick-borne encephalitis as a model. Journal of Virology 63: 564-571.

Monath TP (1986) Pathobiology of the flaviviruses. In: Schlesinger S and Schlesinger MJ (eds) The Togaviridae and the Flaviviridae, pp 375-440. New York: Plenum Press.

Monath TP (ed) (1988) The Arboviruses: Ecology and Epidemiology, vols I-V. Boca Raton, FL: CRC Press.

Monath TP and Heinz FX (1996) Flaviviruses. In: Fields BN, Knipe DM, Chanock RM, Melnick JL, Monath TP and Roizman B (cds) Virology, 3rd edn, pp 961-1034. Philadelphia: Lippincott-Raven Press.

Murali-Krishna K, Ravi V and Manjunath R (1996) Protection of adult but not newborn mice against lethal intracerebral challenge with Japanese encephalitis virus by adoptively transferred virus-specific cytotoxic T lymphocytes: requirement for I.3T4+ T cells. Journal of General Virology 77: 705-714.

Rey FA, Heinz FX, Mandl C, Kunz C and Harrison S

(1995) The envelope glycoprotein from tick-borne encephalitis virus at 2 angstrom resolution. Nature 375: 291-298.

Rico-Hesse R (1990) Molecular evolution and distribution of dengue viruses type 1 and 2 in nature. Virology 174: 479-493.

Rice CM, Lenches EM, Eddy SR, Shin SJ, Sheets RL and Strauss JH (1985) Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science 229: 726-733.

Roehrig JT, Johnson AJ, Hunt AR, Beaty BJ and Mathews JH (1992) Enhancement of the antibody response to flavivirus B-cell epitopes by using homologous or heterologous T-cell epitopes. Journal of Virology 66: 3385-3390.

Sangster MK, Urosevic N, Mansfield JP, Mackenzie JS and Shellam GR (1994) Mapping the Flv locus controlling resistance to flaviviruses on mouse chromosome 5. Journal of Virology 68: 448-452.

Shi PY, Li W and Brinton MA (1996) Cell proteins bind specifically to West Nile Virus minus-strand 3' stem-loop RNA. Journal of Virology 70: 6278-6286.

Tsai TF (1994) Japanese encephalitis vaccines. In: Plotkin SA and Mortimer EA (eds) Vaccines, 2nd edn, pp 671 — 713. Philadelphia: WB Saunders.

Venugopal K and Gould EA (1994) Towards a new generation of Flavivirus vaccines. Vaccine 12: 966-975.

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