Discovery and characterization of a newly emerged DENV serotype.

Dengue virus (DENV) is a mosquito-transmitted flavivirus that presents a substantial threat to public health worldwide. One third of the global population is at risk of infection and over 400 million cases of dengue are reported per year. DENV is maintained in two transmission cycles: a sylvatic cycle between mosquitos and non-human primates (NHP), and an urban cycle between mosquitos and human hosts. The human-endemic lineages of DENV-1-4 each emerged from sylvatic ancestors maintained in a cycle between NHP and arboreal Aedes mosquitoes. Ancestral strains are still persisting in both Southeast Asia and West Africa, posing a risk for the contemporary emergence of sylvatic strains into the human population. In this study I describe the discovery and characterization of a novel DENV, isolated from a febrile patient in the Malaysian state of Sarawak, which presumably represents the prototype virus of a new dengue serotype. A complete genetic and serologic analysis was performed to characterize this isolate and to demonstrate that it represents a distinct virus among the other members of the DENV serogroup. The infection was assessed in a NHP model using rhesus macaques to study pathogenesis and homotypic and heterotypic responses to this novel DENV. A productive infection in NHP was demonstrated, as well the ability of this host to transmit the virus to mosquitoes, which implies the virus can be sustained a transmission cycle in nature. Furthermore, the vector competence of Aedes aegypti and Aedes albopictus mosquitoes, the two main vectors of human-endemic DENV, was evaluated. The potential of these vectors to be infected and transmit the novel virus was demonstrated. Initial structural studies were performed to determine molecular differences could be present in this novel DENV compared to the other DENV serotypes. Collectively, my study describes the emergence of a novel DENV serotype and its biological characteristics. It also brings new insights to the future development of diagnostics, therapeutics and vaccines.