Volume 76, Issue 1
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Dengue infection is an important public health issue worldwide. The ChimeriVax™-Dengue (CYD) vaccine uses yellow fever (YF) 17D vaccine as a live vector. Dendritic cells (DCs) play a key role in initiating immune responses and could be an important primary target of dengue infection. We investigated the consequences of CYD infection of DCs on their activation/maturation and cytokine production. In CYD-infected DCs, we observed an up-regulation of HLA-DR, CD80, CD86, and CD83. Cells exposed to CYD secreted type I interferons, monocyte chemoattractant protein 1 (MCP-1)/CC chemokine ligand 2 (CCL-2), interleukin-6 (IL-6), and low amounts of tumor necrosis factor-α (TNF-α), but no IL-10, IL-12, or IL-1α. Parental dengue viruses induced a similar array of cytokines, but more TNF-α, less IL-6, and less MCP-1/CCL-2 than induced by CYD. Chimeras thus induced DCs maturation and a controlled response accompanied by limited inflammatory cytokine production and consistent expression of anti-viral interferons, in agreement with clinical observations of safety and immunogenicity.


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  1. Pinheiro FP, Corber SJ, 1997. Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat Q 50 : 161–169. [Google Scholar]
  2. Rothman AL, Ennis FA, 1999. Immunopathogenesis and dengue hemorrhagic fever. Virology 257 : 1–6. [Google Scholar]
  3. Lai CJ, Monath TP, 2003. Chimeric flaviviruses: novel vaccines against dengue fever, tick-borne encephalitis, and Japanese encephalitis. Adv Virus Res 61 : 469–509. [Google Scholar]
  4. Monath TP, Guirakhoo F, Nichols R, Yoksan S, Schrader R, Murphy C, Blum P, Woodward S, McCarthy K, Mathis D, Johnson C, Bedford P, 2003. Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen. J Infect Dis 188 : 1213–1230. [Google Scholar]
  5. Guirakhoo F, Arroyo J, Pugachev KV, Miller C, Zhang ZX, Weltzin R, Georgakopoulos K, Catalan J, Ocran S, Soike K, Ratterree M, Monath TP, 2001. Construction, safety, and immunogenicity in nonhuman primates of a chimeric yellow fever-dengue virus tetravalent vaccine. J Virol 75 : 7290–7304. [Google Scholar]
  6. Jones T, 2004. Technology evaluation: ChimeriVax-DEN, Acambis/Aventis. Curr Opin Mol Ther 6 : 443–450. [Google Scholar]
  7. Lei HY, Yeh TM, Liu HS, Lin YS, Chen SH, Liu CC, 2001. Immunopathogenesis of dengue virus infection. J Biomed Sci 8 : 377–388. [Google Scholar]
  8. Chaturvedi UC, Agarwal R, Elbishbishi EA, Mustafa AS, 2000. Cytokine cascade in dengue hemorrhagic fever: implications for pathogenesis. FEMS Immunol Med Microbiol 28 : 183–188. [Google Scholar]
  9. Rothman AL, 2004. Dengue: defining protective versus pathologic immunity. J Clin Invest 113 : 946–951. [Google Scholar]
  10. Halstead SB, O’Rourke EJ, Allison AC, 1977. Dengue viruses and mononuclear phagocytes. II. Identity of blood and tissue leukocytes supporting in vitro infection. J Exp Med 46 : 218–229. [Google Scholar]
  11. Scott RM, Nisalak A, Cheamudon U, Seridhoranakul S, Nimmannitya S, 1980. Isolation of dengue viruses from peripheral blood leukocytes of patients with hemorrhagic fever. J Infect Dis 141 : 1–6. [Google Scholar]
  12. Wu SJ, Grouard-Vogel G, Sun W, Mascola JR, Brachtel E, Putvatana R, Louder MK, Filgueira L, Marovich MA, Wong HK, Blauvelt A, Murphy GS, Robb ML, Innes BL, Birx DL, Hayes CG, Frankel SS, 2000. Human skin Langerhans cells are targets of dengue virus infection. Nat Med 6 : 816–820. [Google Scholar]
  13. Ho LJ, Wang JJ, Shaio MF, Kao CL, Chang DM, Han SW, Lai JH, 2001. Infection of human dendritic cells by dengue virus causes cell maturation and cytokine production. J Immunol 166 : 1499–1506. [Google Scholar]
  14. Marovich M, Grouard-Vogel G, Louder M, Eller M, Sun W, Wu SJ, Putvatana R, Murphy G, Tassaneetrithep B, Burgess T, Birx D, Hayes C, Schlesinger-Frankel S, Mascola J, 2001. Human dendritic cells as targets of dengue virus infection. Investig Dermatol Symp Proc 6 : 219–224. [Google Scholar]
  15. Le Bon A, Tough DF, 2002. Links between innate and adaptive immunity via type I interferon. Curr Opin Immunol 14 : 432–436. [Google Scholar]
  16. Santini SM, Di Pucchio T, Lapenta C, Parlato S, Logozzi M, Belardelli F, 2002. The natural alliance between type I interferon and dendritic cells and its role in linking innate and adaptive immunity. J Interferon Cytokine Res 22 : 1071–1080. [Google Scholar]
  17. Bonjardin CA, 2005. Interferons (IFNs) are key cytokines in both innate and adaptive antiviral immune responses and viruses counteract IFN action. Microbes Infect 7 : 569–578. [Google Scholar]
  18. Banchereau J, Steinman RM, 1998. Dendritic cells and the control of immunity. Nature 392 : 245–252. [Google Scholar]
  19. Sanchez V, Hessler C, DeMontfort A, Lang J, Guy B, 2006. Comparison by flow cytometry of immune changes induced in human monocyte-derived dendritic cells upon infection with dengue 2 live attenuated vaccine or 16681 parental strain. Immunol Med Microbiol 46 : 113–123. [Google Scholar]
  20. Libraty DH, Pichyangkul S, Ajariyakhajorn C, Endy TP, Ennis FA, 2001. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J Virol 75 : 3501–3508. [Google Scholar]
  21. Palmer DR, Sun P, Celluzzi C, Bisbing J, Pang S, Sun W, Marovich MA, Burgess T, 2005. Differential effects of dengue virus on infected and bystander dendritic cells. J Virol 79 : 2432–2439. [Google Scholar]
  22. Rossi D, Zlotnik A, 2000. The biology of chemokines and their receptors. Annu Rev Immunol 18 : 217–242. [Google Scholar]
  23. Lusso P, 2000. Chemokines and viruses: the dearest enemies. Virology 273 : 228–240. [Google Scholar]
  24. Chen YC, Wang SY, 2002. Activation of terminally differentiated human monocytes/macrophages by dengue virus: productive infection, hierarchical production of innate cytokines and chemokines, and the synergistic effect of lipopolysaccharide. J Virol 76 : 9877–9887. [Google Scholar]
  25. Bosch I, Xhaja K, Estevez L, Raines G, Melichar H, Warke RV, Fournier MV, Ennis FA, Rothman AL, 2002. Increased production of interleukin-8 in primary human monocytes and in human epithelial and endothelial cell lines after dengue virus challenge. J Virol 76 : 5588–5597. [Google Scholar]
  26. Moreno-Altamirano MM, Romano M, Legorreta-Herrera M, Sanchez-Garcia FJ, Colston MJ, 2004. Gene expression in human macrophages infected with dengue virus serotype-2. Scand J Immunol 60 : 631–638. [Google Scholar]
  27. Medin CL, Fitzgerald KA, Rothman AL, 2005. Dengue virus nonstructural protein NS5 induces interleukin-8 transcription and secretion. J Virol 79 : 11053–11061. [Google Scholar]
  28. Lin CF, Chiu SC, Hsiao YL, Wan SW, Lei HY, Shiau AL, Liu HS, Yeh TM, Chen SH, Liu CC, Lin YS, 2005. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol 174 : 395–403. [Google Scholar]
  29. Brandler S, Brown N, Ermak TH, Mitchell F, Parsons M, Zhang Z, Lang J, Monath TP, Guirakhoo F, 2005. Replication of chimeric yellow fever virus-dengue serotype 1–4 virus vaccine strains in dendritic and hepatic cells. Am J Trop Med Hyg 72 : 74–81. [Google Scholar]
  30. Navarro-Sanchez E, Altmeyer R, Amara A, Schwartz O, Fieschi F, Virelizier JL, Arenzana-Seisdedos F, Despres P, 2003. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep 4 : 723–728. [Google Scholar]
  31. Tassaneetrithep B, Burgess TH, Granelli-Piperno A, Trumpf-heller C, Finke J, Sun W, Eller MA, Pattanapanyasat K, Sarasombath S, Birx DL, Steinman RM, Schlesinger S, Marovich MA, 2003. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med 197 : 823–829. [Google Scholar]
  32. Barba-Spaeth G, Longman RS, Albert ML, Rice CM, 2005. Live attenuated yellow fever 17D infects human DCs and allows for presentation of endogenous and recombinant T cell epitopes. J Exp Med 202 : 1179–1184. [Google Scholar]
  33. Ho LJ, Shaio MF, Chang DM, Liao CL, Lai JH, 2004. Infection of human dendritic cells by dengue virus activates and primes T cells towards Th0-like phenotype producing both Th1 and Th2 cytokines. Immunol Invest 33 : 423–437. [Google Scholar]
  34. Querec T, Bennouna S, Alkan S, Laouar Y, Gorden K, Flavell R, Akira S, Ahmed R, Pulendran B, 2006. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity. J Exp Med 203 : 413–424. [Google Scholar]
  35. Shresta S, Kyle JL, Snider HM, Basavapatna M, Beatty PR, Harris E, 2004. Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T-and B-cell-dependent immunity are less critical. J Virol 78 : 2701–2710. [Google Scholar]
  36. Hober D, Poli L, Roblin B, Gestas P, Chungue E, Granic G, Imbert P, Pecarere JL, Vergez-Pascal R, Wattre P, 1993. Serum levels of tumor necrosis factor-alpha (TNF-alpha), inter-leukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg 48 : 324–331. [Google Scholar]
  37. Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Lew R, Innis BL, Kurane I, Rothman AL, Ennis FA, 1999. Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity. J Infect Dis 179 : 755–762. [Google Scholar]
  38. Green S, Vaughn DW, Kalayanarooj S, Nimmannitya S, Suntayakorn S, Nisalak A, Rothman AL, Ennis FA, 1999. Elevated plasma interleukin-10 levels in acute dengue correlate with disease severity. J Med Virol 59 : 329–334. [Google Scholar]
  39. Azeredo EL, Zagne SM, Santiago MA, Gouvea AS, Santana AA, Neves-Souza PC, Nogueira RM, Miagostovich MP, Kubelka CF, 2001. Characterisation of lymphocyte response and cytokine patterns in patients with dengue fever. Immunobiology 204 : 494–507. [Google Scholar]
  40. Chen LC, Lei HY, Liu CC, Shiesh SC, Chen SH, Liu HS, Lin YS, Wang ST, Shyu HW, Yeh TM, 2006. Correlation of serum levels of macrophage migration inhibitory factor with disease severity and clinical outcome in dengue patients. Am J Trop Med Hyg 74 : 142–147. [Google Scholar]
  41. Galler R, Marchevsky RS, Caride E, Almeida LF, Yamamura AM, Jabor AV, Motta MC, Bonaldo MC, Coutinho ES, Freire MS, 2005. Attenuation and immunogenicity of recombinant yellow fever 17D-dengue type 2 virus for rhesus monkeys. Braz J Med Biol Res 38 : 1835–1846. [Google Scholar]
  42. Guirakhoo F, Pugachev K, Zhang Z, Myers G, Levenbook I, Draper K, Lang J, Ocran S, Mitchell F, Parsons M, Brown N, Brandler S, Fournier C, Barrere B, Rizvi F, Travassos A, Nichols R, Trent D, Monath T, 2004. Safety and efficacy of chimeric yellow fever-dengue virus tetravalent vaccine formulations in nonhuman primates. J Virol 78 : 4761–4775. [Google Scholar]

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  • Received : 15 Feb 2006
  • Accepted : 26 Sep 2006

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