Volume 89, Issue 6
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645



Dengue virus (DENV) is considered to be the most important arthropod-borne viral disease and causes more than 100 million human infections annually. To further characterize primary DENV infection , rhesus macaques were infected with DENV-1, DENV-2, DENV-3, or DENV-4 and clinical parameters, as well as specificity and longevity of serologic responses, were assessed. Overt clinical symptoms were not present after infection. However, abnormalities in blood biochemical parameters consistent with heart, kidney, and liver damage were observed, and changes in plasma fibrinogen, D-dimers, and protein C indicated systemic activation of the blood coagulation pathway. Significant homotypic and heterotypic serum immunoglobulins were present in all animals, and IgG persisted for at least 390 days. Serum neutralizing antibody responses were highly serotype specific by day 120. However, some heterotypic neutralizing activity was noted in infected animals. Identification of serotype-specific host responses may help elucidate mechanisms that mediate severe DENV disease after reinfection.


Article metrics loading...

Loading full text...

Full text loading...



  1. Gubler DJ, Knipe DM, Howley PM, , 2007. Flaviviruses. , eds. Fields Virology. Fifth edition. Philadelphia, PA: Lippincott Williams and Wilkins, 11531252.
  2. Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martinez E, Nathan MB, Pelegrino JL, Simmons C, Yoksan S, Peeling RW, , 2010. Dengue: a continuing global threat. Nat Rev Microbiol 8: S7S16.[Crossref]
  3. Kyle JL, Harris E, , 2008. Global spread and persistence of dengue. Annu Rev Microbiol 62: 7192.[Crossref]
  4. Whitehead SS, Blaney JE, Durbin AP, Murphy BR, , 2007. Prospects for a dengue virus vaccine. Nat Rev Microbiol 5: 518528.[Crossref]
  5. Shepard DS, Undurraga EA, Lees RS, Halasa Y, Lum LC, Ng CW, , 2012. Use of multiple data sources to estimate the economic cost of dengue illness in Malaysia. Am J Trop Med Hyg 87: 796805.[Crossref]
  6. Halstead SB, Palumbo NE, , 1973. Studies on the immunization of monkeys against dengue. II. Protection following inoculation of combinations of viruses. Am J Trop Med Hyg 22: 375381.
  7. Peiris JS, Dittus WP, Ratnayake CB, , 1993. Seroepidemiology of dengue and other arboviruses in a natural population of toque macaques (Macaca sinica) at Polonnaruwa, Sri Lanka. J Med Primatol 22: 240245.
  8. Rodhain F, , 1991. The role of monkeys in the biology of dengue and yellow fever. Comp Immunol Microbiol Infect Dis 14: 919.[Crossref]
  9. Halstead SB, Shotwell H, Casals J, , 1973. Studies on the pathogenesis of dengue infection in monkeys. I. Clinical laboratory responses to primary infection. J Infect Dis 128: 714.[Crossref]
  10. Halstead SB, Shotwell H, Casals J, , 1973. Studies on the pathogenesis of dengue infection in monkeys. II. Clinical laboratory responses to heterologous infection. J Infect Dis 128: 1522.[Crossref]
  11. Onlamoon N, Noisakran S, Hsiao HM, Duncan A, Villinger F, Ansari AA, Perng GC, , 2010. Dengue virus-induced hemorrhage in a nonhuman primate model. Blood 115: 18231834.[Crossref]
  12. Cassetti MC, Durbin A, Harris E, Rico-Hesse R, Roehrig J, Rothman A, Whitehead S, Natarajan R, Laughlin C, , 2009. Report of an NIAID workshop on dengue animal models. Vaccine 28: 42294234.[Crossref]
  13. Raviprakash K, Wang D, Ewing D, Holman DH, Block K, Woraratanadharm J, Chen L, Hayes C, Dong JY, Porter K, , 2008. A tetravalent dengue vaccine based on a complex adenovirus vector provides significant protection in rhesus monkeys against all four serotypes of dengue virus. J Virol 82: 69276934.[Crossref]
  14. Durbin AP, Karron RA, Sun W, Vaughn DW, Reynolds MJ, Perreault JR, Thumar B, Men R, Lai CJ, Elkins WR, Chanock RM, Murphy BR, Whitehead SS, , 2001. Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3′-untranslated region. Am J Trop Med Hyg 65: 405413.
  15. Blaney JE, Jr Matro JM, Murphy BR, Whitehead SS, , 2005. Recombinant, live-attenuated tetravalent dengue virus vaccine formulations induce a balanced, broad, and protective neutralizing antibody response against each of the four serotypes in rhesus monkeys. J Virol 79: 55165528.[Crossref]
  16. Bernardo L, Izquierdo A, Prado I, Rosario D, Alvarez M, Santana E, Castro J, Martínez R, Rodríguez R, Morier L, Guillén G, Guzmán MG, , 2008. Primary and secondary infections of Macaca fascicularis monkeys with Asian and American genotypes of dengue virus 2. Clin Vaccine Immunol 15: 439446.[Crossref]
  17. Freire MS, Marchevsky RS, Almeida LF, Yamamura AM, Caride EC, Brindeiro PA, Motta MC, Nogueira RM, Kubelka CF, Bonaldo MC, Galler R, , 2007. Wild dengue virus types 1, 2 and 3 viremia in rhesus monkeys. Mem Inst Oswaldo Cruz 102: 203208.[Crossref]
  18. Kochel TJ, Watts DM, Gozalo AS, Ewing DF, Porter KR, Russell KL, , 2005. Cross-Serotype neutralization of dengue virus in Aotus nancymae monkeys. J Infect Dis 191: 10001004.[Crossref]
  19. Martín J, Hermida L, Castro J, Lazo L, Martínez R, Gil L, Romero Y, Puente P, Zaragoza S, Cosme K, Guzmán MG, Cardosa J, Guillén G, , 2009. Viremia and antibody response in green monkeys (Chlorocebus aethiops sabaeus) infected with dengue virus type 2: a potential model for vaccine testing. Microbiol Immunol 53: 216223.[Crossref]
  20. Martın J, Hermida L, Castro J, Romero Y, Cardosa J, Guillen G, , 2009. Viremia and the magnitude of the immune response upon infection of green monkeys with dengue virus type 2 are strain-dependent. Curr Microbiol 59: 579583.[Crossref]
  21. Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, , 2007. Efficacy of a live attenuated tetravalent candidate dengue vaccine in naïve and previously infected macaques. Vaccine 25: 54095416.[Crossref]
  22. Koraka P, Benton S, van Amerongen G, Stittelaar KJ, Osterhaus AD, , 2007. Characterization of humoral and cellular immune responses in cynomolgus macaques upon primary and subsequent heterologous infections with dengue viruses. Microbes Infect 9: 940946.[Crossref]
  23. Ferguson M, Johnes S, Li L, Heath A, Barrett A, , 2008. Effect of genomic variation in the challenge virus on the neutralization titres of recipients of inactivated JE vaccines–report of a collaborative study on PRNT50 assays for Japanese encephalitis virus (JE) antibodies. Biologicals 36: 111116.[Crossref]
  24. Committee for the Update of the Guide for the Care and Use of Laboratory Animals, 2011. Guide for the Care and Use of Laboratory Animals. Eighth edition. Washington, DC: National Academies of Science Press.
  25. Bossart KN, Rockx B, Feldmann F, Brining D, Scott D, LaCasse R, Geisbert JB, Feng YR, Chan YP, Hickey AC, Broder CC, Feldmann H, Geisbert TW, , 2012. A Hendra virus G glycoprotein subunit vaccine protects African green monkeys from Nipah virus challenge. Sci Transl Med 4: 146ra107.[Crossref]
  26. Lee JI, Shin JS, Lee JE, Jung WY, Lee G, Kim MS, Park CG, Kim SJ, , 2012. Reference values of hematology, chemistry, electrolytes, blood gas, coagulation time, and urinalysis in the Chinese rhesus macaques (Macaca mulatta). Xenotransplantation 19: 244248.[Crossref]
  27. Messer WB, Yount B, Hacker KE, Donaldson EF, Huynh JP, de Silva AM, Baric RS, , 2012. Development and characterization of a reverse genetic system for studying dengue virus serotype 3 strain variation and neutralization. PLoS Negl Trop Dis 6: e1486.[Crossref]
  28. Henchal EA, Gentry MK, McCown JM, Brandt WE, , 1982. Dengue virus-specific and flavivirus group determinants identified with monoclonal antibodies by indirect immunofluorescence. Am J Trop Med Hyg 31: 830836.
  29. Geisbert TW, Daddario-DiCaprio KM, Hickey AC, Smith MA, Chan YP, Wang LF, Mattapallil JJ, Geisbert JB, Bossart KN, Broder CC, , 2010. Development of an acute and highly pathogenic nonhuman primate model of Nipah virus infection. PLoS ONE 5: e10690.[Crossref]
  30. Pang T, Cardosa MJ, Guzman MG, , 2007. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol 85: 4345.[Crossref]
  31. Halstead SB, Marchette NJ, Sung Chow JS, Lolekha S, , 1976. Dengue virus replication enhancement in peripheral blood leukocytes from immune human beings. Proc Soc Exp Biol Med 151: 136139.[Crossref]
  32. Potts JA, Rothman AL, , 2008. Clinical and laboratory features that distinguish dengue from other febrile illnesses in endemic populations. Trop Med Int Health 13: 13281340.[Crossref]
  33. Deparis X, Murgue B, Roche C, Cassar O, Chungue E, , 1998. Changing clinical and biological manifestations of dengue during the dengue-2 epidemic in French Polynesia in 1996/97: description and analysis in a prospective study. Trop Med Int Health 3: 859865.[Crossref]
  34. Wilder-Smith A, Earnest A, Paton NI, , 2004. Use of simple laboratory features to distinguish the early stage of severe acute respiratory syndrome from dengue fever. Clin Infect Dis 39: 18181823.[Crossref]
  35. McBride WJ, Mullner H, LaBrooy JT, Wronski I, , 1998. The 1993 dengue 2 epidemic in Charters Towers, North Queensland: clinical features and public health impact. Epidemiol Infect 121: 151156.[Crossref]
  36. Lee IK, Lee WH, Liu JW, Yang KD, , 2010. Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. Int J Infect Dis 14: e919e922.[Crossref]
  37. Marques N, Gan VC, Leo YS, , 2013. Dengue myocarditis in Singapore: two case reports. Infection 41: 709714.[Crossref]
  38. Lima EQ, Gorayeb FS, Zanon JR, Nogueira ML, Ramalho HJ, Burdmann EA, , 2007. Dengue haemorrhagic fever-induced acute kidney injury without hypotension, haemolysis or rhabdomyolysis. Nephrol Dial Transplant 22: 33223326.[Crossref]
  39. Lima EQ, Nogueira ML, , 2008. Viral hemorrhagic fever-induced acute kidney injury. Semin Nephrol 28: 409415.[Crossref]
  40. Mehra N, Patel A, Abraham G, Reddy YN, , 2012. Acute kidney injury in dengue fever using Acute Kidney Injury Network criteria: incidence and risk factors. Trop Doct 42: 160162.[Crossref]
  41. de Macedo FC, Nicol AF, Cooper LD, Yearsley M, Pires AR, Nuovo GJ, , 2006. Histologic, viral, and molecular correlates of dengue fever infection of the liver using highly sensitive immunohistochemistry. Diagn Mol Pathol 15: 223228.[Crossref]
  42. Jessie K, Fong MY, Devi S, Lam SK, Wong KT, , 2004. Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 189: 14111418.[Crossref]
  43. Tristao-Sa R, Kubelka CF, Zandonade E, Zagne SM, Rocha N de S, Zagne LO, Araujo NF, Amin B, Fazoli F, Souza LJ, Cruz OG, Cunha RV, Nascimento D, Froes IB, Nogueira RM, , 2012. Clinical and hepatic evaluation in adult dengue patients: a prospective two-month cohort study. Rev Soc Bras Med Trop 45: 675681.[Crossref]
  44. Mammen EF, , 1992. Coagulation abnormalities in liver disease. Hematol Oncol Clin North Am 6: 12471257.
  45. Amitrano L, Guardascione MA, Brancaccio V, Balzano A, , 2002. Coagulation disorders in liver disease. Semin Liver Dis 22: 8396.[Crossref]

Data & Media loading...

Supplementary Data

Supplementary PDF

  • Received : 19 Mar 2013
  • Accepted : 15 Jul 2013

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error