Dengue Virus Type-3 (DENV-3) Evolution and Epidemic activity in Indonesia

Dengue viruses are one of today’s most significant vector-borne disease agents threatening human health throughout the tropics and subtropics, infecting hundreds of millions of people annually. Dengue is primarily transmitted by Aedes aegypti mosquitoes. There are four known serotypes circulating in humans (DENV-1 to -4) all of which can cause a febrile illness known as dengue fever that can progress to more severe and potentially fatal disease involving hemorrhage or shock (DHF/DSS). We report here follow up sequence data on DENV-3 strains isolated during epidemics that occurred in Indonesia between 1976 and 1979. The epidemics began with the detection of fatal DHF/DSS associated with DENV-3 in Jakarta in Jan-Mar, 1976. The virus spread to Bantul, Central Java in Oct, 1976, and to Surabaya, East Java and Pontianak, West Kalimantan in 1977. All of these were explosive epidemics with associated severe disease. A smaller outbreak with more sporadic transmission, milder illness and much lower viremia levels occurred in Sleman, Central Java in 1978. Viruses were isolated by one of us (co-author, Duane J. Gubler; Duke-NUS Graduate Medical School) from all of these epidemics and stored in infected mosquitoes at -70 C for nearly 40 years. The viruses had not been passaged in mice nor mammalian cell cultures. Full genomic sequence analysis suggests that a single strain of DENV-3 with greater epidemic potential and possibly virulence emerged in Jakarta and spread rapidly along the main transportation routes to Central and East Java, and to Kalimantan. Interestingly, the Sleman DENV-3 viruses were genetically distinct, belonging to a separate clade from the other strains. There were two unique Bantul isolates that also belonged to the Sleman clade, suggesting that the Sleman virus descended from these Bantul viruses. Our findings emphasize the importance of dengue evolution and genetic variation as a contributor to epidemic intensity and severe dengue disease.