Historical records describe a disease in North America that clinically resembled dengue haemorrhagic fever during the latter part of the slave-trading period. However, the dengue epidemic that occurred in Cuba in 1981 was the first laboratory-confirmed and clinically diagnosed outbreak of dengue haemorrhagic fever in the Americas. At that time, the presumed source of the dengue type 2 strain isolated during this epidemic was considered controversial, partly because of the limited sequence data and partly because the origin of the virus appeared to be southern Asia. Here, we present a molecular characterisation at the whole-genome level of the original strains isolated at different time points during the epidemic. Phylogenetic trees constructed using Bayesian methods indicated that 1981 Cuban strains group within the Asian 2 genotype. In addition, the study revealed that viral evolution occurred during the epidemic – a fact that could be related to the increasing severity from month to month. Moreover, the Cuban strains exhibited particular amino acid substitutions that differentiate them from the New Guinea C prototype strain as well as from dengue type 2 strains isolated globally.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Alvarez M, Guzman MG, Rosario D, Vazquez S, Pelegrino JL, Sariol CA, Kouri G (1996) Secuenciacion directa de un producto amplificado de una muestra de suero. [Direct sequencing of an amplified product from a serum sample]. Revista cubana de medicina tropical 48:53–55
Anez G, Morales-Betoulle ME, Rios M (2011) Circulation of different lineages of dengue virus type 2 in Central America, their evolutionary time-scale and selection pressure analysis. PloS One 6:e27459
Armada Gessa JA, Figueredo Gonzalez R (1986) Application of environmental management principles in the program for eradication of Aedes (Stegomyia) aegypti (Linnaeus, 1762) in the Republic of Cuba, 1984. Bull Pan Am Health Organ 20:186–193
Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O, Myers MF, George DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Farrar JJ, Hay SI (2013) The global distribution and burden of dengue. Nature 496:504–507
Bravo JR, Guzman MG, Kouri GP (1987) Why dengue haemorrhagic fever in Cuba? 1. Individual risk factors for dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Trans R Soc Trop Med Hyg 81:816–820
Bray M, Men R, Tokimatsu I, Lai CJ (1998) Genetic determinants responsible for acquisition of dengue type 2 virus mouse neurovirulence. J Virol 72:1647–1651
Cantelar de Francisco N, Fernandez A, Albert Molina L, Perez Balbis E (1981) Survey of dengue in Cuba. 1978–1979. Revista cubana de medicina tropical 33:72–78
Christenbury JG, Aw PP, Ong SH, Schreiber MJ, Chow A, Gubler DJ, Vasudevan SG, Ooi EE, Hibberd ML (2010) A method for full genome sequencing of all four serotypes of the dengue virus. J Virol Methods 169:202–206
Diaz FJ, Black WC IV, Farfan-Ale JA, Lorono-Pino MA, Olson KE, Beaty BJ (2006) Dengue virus circulation and evolution in Mexico: a phylogenetic perspective. Arch Med Res 37:760–773
Drummond AJ, Rambaut A (2007) BEAST: bayesian evolutionary analysis by sampling trees. BMC Evol Biol 7:214
Falconar AK (1999) Identification of an epitope on the dengue virus membrane (M) protein defined by cross-protective monoclonal antibodies: design of an improved epitope sequence based on common determinants present in both envelope (E and M) proteins. Arch Virol 144:2313–2330
Foster JE, Bennett SN, Carrington CV, Vaughan H, McMillan WO (2004) Phylogeography and molecular evolution of dengue 2 in the Caribbean basin, 1981–2000. Virology 324:48–59
Gadkari RA, Srinivasan N (2010) Prediction of protein-protein interactions in dengue virus coat proteins guided by low resolution cryoEM structures. BMC Struct Biol 10:17
Gregg MB, Hinman AR, Craven RB (1978) The Russian flu. Its history and implications for this year’s influenza season. JAMA: J Am Med Assoc 240:2260–2263
Gubler DJ, Clark GG (1995) Dengue/dengue hemorrhagic fever: the emergence of a global health problem. Emerg Infect Dis 1:55–57
Guzman MG, Deubel V, Pelegrino JL, Rosario D, Marrero M, Sariol C, Kouri G (1995) Partial nucleotide and amino acid sequences of the envelope and the envelope/nonstructural protein-1 gene junction of four dengue-2 virus strains isolated during the 1981 Cuban epidemic. Am J Trop Med Hyg 52:241–246
Guzman MG, Kouri G, Valdes L, Bravo J, Vazquez S, Halstead SB (2002) Enhanced severity of secondary dengue-2 infections: death rates in 1981 and 1997 Cuban outbreaks. Revista panamericana de salud publica = Pan Am J Public Health 11:223–227
Guzman MG, Alvarez M, Rodriguez-Roche R, Bernardo L, Montes T, Vazquez S, Morier L, Alvarez A, Gould EA, Kouri G, Halstead SB (2007) Neutralizing antibodies after infection with dengue 1 virus. Emerg Infect Dis 13:282–286
Guzman MG (2012) Thirty years after the Cuban hemorrhagic dengue epidemic of 1981. MEDICC Rev 14:46–51
Halstead SB, Streit TG, Lafontant JG, Putvatana R, Russell K, Sun W, Kanesa-Thasan N, Hayes CG, Watts DM (2001) Haiti: absence of dengue hemorrhagic fever despite hyperendemic dengue virus transmission. Am J Trop Med Hyg 65:180–183
Halstead SB (2006) Dengue in the Americas and Southeast Asia: do they differ? Revista panamericana de salud publica = Pan Am J Public Health 20:407–415
Huelsenbeck JP, Ronquist F (2001) MRBAYES: bayesian inference of phylogenetic trees. Bioinformatics 17:754–755
Irie K, Mohan PM, Sasaguri Y, Putnak R, Padmanabhan R (1989) Sequence analysis of cloned dengue virus type 2 genome (New Guinea-C strain). Gene 75:197–211
Kouri G, Guzman MG, Bravo J (1986) Hemorrhagic dengue in Cuba: history of an epidemic. Bull Pan Am Health Organ 20:24–30
Kouri GP, Guzman MG, Bravo JR (1987) Why dengue haemorrhagic fever in Cuba? 2. An integral analysis. Trans R Soc Trop Med Hyg 81:821–823
Lee E, Weir RC, Dalgarno L (1997) Changes in the dengue virus major envelope protein on passaging and their localization on the three-dimensional structure of the protein. Virology 232:281–290
Leitmeyer KC, Vaughn DW, Watts DM, Salas R, Villalobos de Chacon I, Ramos C, Rico-Hesse R (1999) Dengue virus structural differences that correlate with pathogenesis. J Virol 73:4738–4747
Li L, Lok SM, Yu IM, Zhang Y, Kuhn RJ, Chen J, Rossmann MG (2008) The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science 319:1830–1834
Lok SM, Ng ML, Aaskov J (2001) Amino acid and phenotypic changes in dengue 2 virus associated with escape from neutralisation by IgM antibody. J Med Virol 65:315–323
Mazumder R, Hu ZZ, Vinayaka CR, Sagripanti JL, Frost SD, Kosakovsky Pond SL, Wu CH (2007) Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines. Virus Genes 35:175–186
Modis Y, Ogata S, Clements D, Harrison SC (2005) Variable surface epitopes in the crystal structure of dengue virus type 3 envelope glycoprotein. J Virol 79:1223–1231
PAHO (1990) Dengue hemorrhagic fever in Venezuela. Epidemiol Bull 11:7–9
Rice CM, Lenches EM, Eddy SR, Shin SJ, Sheets RL, Strauss JH (1985) Nucleotide sequence of yellow fever virus: implications for flavivirus gene expression and evolution. Science 229:726–733
Rico-Hesse R, Harrison LM, Salas RA, Tovar D, Nisalak A, Ramos C, Boshell J, de Mesa MT, Nogueira RM, da Rosa AT (1997) Origins of dengue type 2 viruses associated with increased pathogenicity in the Americas. Virology 230:244–251
Rico-Hesse R (2003) Microevolution and virulence of dengue viruses. Adv Virus Res 59:315–341
Rodriguez-Roche R, Alvarez M, Gritsun T, Halstead S, Kouri G, Gould EA, Guzman MG (2005) Virus evolution during a severe dengue epidemic in Cuba, 1997. Virology 334:154–159
Rodriguez-Roche R, Alvarez M, Gritsun T, Rosario D, Halstead S, Kouri G, Gould EA, Guzman MG (2005) Dengue virus type 2 in Cuba, 1997: conservation of E gene sequence in isolates obtained at different times during the epidemic. Arch Virol 150:415–425
Rodriguez-Roche R, Sanchez L, Burgher Y, Rosario D, Alvarez M, Kouri G, Halstead SB, Gould EA, Guzman MG (2011) Virus role during intraepidemic increase in dengue disease severity. Vector Borne Zoonotic Dis 11:675–681
Rodriguez-Roche R, Villegas E, Cook S, Poh Kim PA, Hinojosa Y, Rosario D, Villalobos I, Bendezu H, Hibberd ML, Guzman MG (2012) Population structure of the dengue viruses, Aragua, Venezuela, 2006-2007. Insights into dengue evolution under hyperendemic transmission. Infect Genet Evol: J Mol Epidemiol Evol Genet Infect Dis 12:332–344
Rodriguez-Roche R, Gould EA (2013) Understanding the dengue viruses and progress towards their control. Biomed Res Int 2013:690835
Roehrig JT, Risi PA, Brubaker JR, Hunt AR, Beaty BJ, Trent DW, Mathews JH (1994) T-helper cell epitopes on the E-glycoprotein of dengue 2 Jamaica virus. Virology 198:31–38
Salda LT, Parquet MD, Matias RR, Natividad FF, Kobayashi N, Morita K (2005) Molecular epidemiology of dengue 2 viruses in the Philippines: genotype shift and local evolution. Am J Trop Med Hyg 73:796–802
San Martin JL, Brathwaite O, Zambrano B, Solorzano JO, Bouckenooghe A, Dayan GH, Guzman MG (2010) The epidemiology of dengue in the Americas over the last three decades: a worrisome reality. Am J Trop Med Hyg 82:128–135
Sariol CA, Pelegrino JL, Martinez A, Arteaga E, Kouri G, Guzman MG (1999) Detection and genetic relationship of dengue virus sequences in seventeen-year-old paraffin-embedded samples from Cuba. Am J Trop Med Hyg 61:994–1000
Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG (1997) The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 24:4876–4882
Twiddy SS, Farrar JJ, Vinh Chau N, Wills B, Gould EA, Gritsun T, Lloyd G, Holmes EC (2002) Phylogenetic relationships and differential selection pressures among genotypes of dengue-2 virus. Virology 298:63–72
Yap TL, Xu T, Chen YL, Malet H, Egloff MP, Canard B, Vasudevan SG, Lescar J (2007) Crystal structure of the dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J Virol 81:4753–4765
We thank Prof. Ernest A. Gould and Prof. Marco Vignuzzi for relevant suggestions and useful comments concerning the manuscript.
This research was supported by the Cuban Ministry of Public Health and the EU 7th Framework-Health Programme (Grant Agreement No. 282378 – DENFREE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
All authors declare no conflicts of interest
About this article
Cite this article
Rodriguez-Roche, R., Hinojosa, Y. & Guzman, M.G. First dengue haemorrhagic fever epidemic in the Americas, 1981: insights into the causative agent. Arch Virol 159, 3239–3247 (2014). https://doi.org/10.1007/s00705-014-2188-y
- Amino Acid Change
- Dengue Virus
- Dengue Fever
- Dengue Haemorrhagic Fever