Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis.

Dengue virus (DENV) is a member of the Flavivirus genus of the Flaviviridae family of enveloped, positive-strand RNA viruses. The Flavivirus genus includes viruses transmitted by mosquitoes and ticks, as well as zoonotic agents with no known arthropod vector. In addition to DENV, flaviviruses that are significant threats to human health include yellow fever virus, West Nile virus (WNV), Japanese encephalitis virus, and tickborne encephalitis virus. The dengue viruses are comprised of four distinct serotypes, DENV1 through DENV4, which are transmitted to humans through the bites of two mosquito species: Aedes aegypti and A. albopictus. DENV causes a wide range of diseases in humans, from the acute febrile illness dengue fever (DF) to life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). DF is a self-limited though debilitating illness characterized by fever, headache, retro-orbital pain, myalgia, arthralgia, and rash. DHF is marked by increased vascular permeability (“plasma leakage”), thrombocytopenia, and hemorrhagic manifestations; DSS occurs when fluid leakage into the interstitial spaces results in shock, which without appropriate treatment may lead to death. Dengue has spread throughout tropical and subtropical regions worldwide over the past several decades, with an estimated 100 million infections and tens of millions of cases occurring annually. DHF/DSS is one of the leading causes of pediatric hospitalization in Southeast Asia, where the syndrome first emerged 50 years ago, and has become endemic to many Latin American countries over the last 25 years (reviewed in references 64 and 184).