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The dengue viruses are members of the genus Flavivirus in the family Flaviviridae. Along with the dengue virus, this genus also includes a number of other viruses transmitted by mosquitoes and ticks that are responsible for human diseases. Flavivirus includes the yellow fever, West Nile, Japanese encephalitis, and tick-borne encephalitis viruses.
In 1943, Ren Kimura and Susumu Hotta first isolated the dengue virus. These two scientists were studying blood samples of patients taken during the 1943 dengue epidemic in Nagasaki, Japan. A year later, Albert B. Sabin and Walter Schlesinger independently isolated the dengue virus. Both pairs of scientists had isolated the virus now referred to as dengue virus 1 (DEN-1). Is DEN-1 the only type of dengue virus?
Dengue infections are caused by four closely related viruses named DEN-1, DEN-2, DEN-3, and DEN-4. These four viruses are called serotypes because each has different interactions with the antibodies in human blood serum. The four dengue viruses are similar — they share approximately 65% of their genomes — but even within a single serotype, there is some genetic variation. Despite these variations, infection with each of the dengue serotypes results in the same disease and range of clinical symptoms.
Are these four viruses all found in the same regions of the world? In the 1970s, both DEN-1 and DEN-2 were found in Central America and Africa, and all four serotypes were present in Southeast Asia. By 2004, however, the geographical distribution of the four serotypes had spread widely. Now all four dengue serotypes circulate together in tropical and subtropical regions around the world (Figure 1). The four dengue serotypes share the same geographic and ecological niche. Where did the dengue viruses first come from? Scientists hypothesize that the dengue viruses evolved in nonhuman primates and jumped from these primates to humans in Africa or Southeast Asia between 500 and 1,000 years ago.
After recovering from an infection with one dengue serotype, a person has immunity against that particular serotype. Does infection with one serotype protect against future dengue infections with the other serotypes? Individuals are protected from infections with the remaining three serotypes for two to three months after the first dengue infection. Unfortunately, it is not long-term protection. After that short period, a person can be infected with any of the remaining three dengue serotypes. Researchers have noticed that subsequent infections can put individuals at a greater risk for severe dengue illnesses than those who have not been previously infected.
The dengue virus genome is a single strand of RNA. It is referred to as positive-sense RNA because it can be directly translated into proteins. The viral genome encodes ten genes (Figure 2). The genome is translated as a single, long polypeptide and then cut into ten proteins.
What are the roles of these ten proteins? Three are structural proteins: the capsid (C), envelope (E), and membrane (M) proteins. Seven are nonstructural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. These nonstructural proteins play roles in viral replication and assembly.
How does the virus behave once it enters the human body? The dengue viral replication process begins when the virus attaches to a human skin cell (Figure 4). After this attachment, the skin cell's membrane folds around the virus and forms a pouch that seals around the virus particle. This pouch is called an endosome. A cell normally uses endosomes to take in large molecules and particles from outside the cell for nourishment. By hijacking this normal cell process, the dengue virus is able to enter a host cell.
Once the virus has entered a host cell, the virus penetrates deeper into the cell while still inside the endosome. How does the virus exit the endosome, and why? Researchers have learned that two conditions are needed for the dengue virus to exit the endosome:
These two conditions allow the virus envelope to fuse with the endosomal membrane, and that process releases the dengue nucleocapsid into the cytoplasm of the cell.
Once it is released into the cell cytoplasm, how does the virus replicate itself? In the cytoplasm, the nucleocapsid opens to uncoat the viral genome. This process releases the viral RNA into the cytoplasm. The viral RNA then hijacks the host cell's machinery to replicate itself. The virus uses ribosomes on the host's rough endoplasmic reticulum (ER) to translate the viral RNA and produce the viral polypeptide. This polypeptide is then cut to form the ten dengue proteins.
The newly synthesized viral RNA is enclosed in the C proteins, forming a nucleocapid. The nucleocapsid enters the rough ER and is enveloped in the ER membrane and surrounded by the M and E proteins. This step adds the viral envelope and protective outer layer. The immature viruses travel through the Golgi apparatus complex, where the viruses mature and convert into their infectious form. The mature dengue viruses are then released from the cell and can go on to infect other cells.
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