Although we cannot see them, smell them or taste them these little assassins reside in the air we breathe, the water we drink and in all of our personal space. They are the tiniest simplest form of life on earth and have the ability to cause epidemics more devastating than war. Viruses are the cause of a lot of miseries such as HIV, H1N1, Polio and SARS. Other viruses such as the West Nile virus, Yellow Fever and Dengue Virus are zoonotic viruses that originally developed in animals but somehow found their way into the human body. Like humans, viruses are part of nature and are believed to have originated even before mankind. The first virus was discovered in the 1890's and since then hundreds of viruses have emerged around the globe many of which are deadly (Samuel 1). Dengue Virus is a mosquito borne viral illness that causes hemorrhagic fever and is endemic to Colombia and other tropical and subtropical areas in South America. It is also known as "break bone fever" because it causes a high fever with extreme pain and stiffness in the joints. (Rigau, 1998). In more serious cases it causes dengue hemorrhagic fever which is of great concern because of its potential lethal complications. The recent incidence increase of this ancient virus in the last 50 years has caused major public health problems. Dengue Virus has had a great emotional and physical impact in the world therefore understating this infectious agent through its life cycle, prevention, treatment, and pathogenesis will give us greater insight into how to fight it.
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Dengue virus, one of the most common insect-borne viruses that affect humans was first identified in Africa but over the years has spread to other parts of the world including South America. It is a highly pathogenic virus that is a member of the family Flaviviradae and genus Flavivirus. The Flaviviradae family includes approximately 70 other viruses that are all primarily transmitted by arthropods (Mukhopadhyay, 2005). Dengue virus has a single stranded positive sense RNA genome and it is classified under the Baltimore class IV. These enveloped viruses, with icosahedral capsids, have a genome which is 11,000 to 12,000 nucleotides long.
The genome has an open reading frame encoding a single polyprotein that consists of a 5'cap, nonstructural proteins, structural proteins and lacks a poly(A) tail on the 3'end. It consists of short non-coding regions on both the 5'and 3' ends and encodes a total of ten proteins, 3 of which are structural and the other 7 are nonstructural. The three structural proteins which are encoded on the amino terminus of the genome are C for nucleocapsid, , prM, which is cleaved by the host protease to form mature virions, and E for the envelope glycoprotein. The other seven nonstructural proteins that aid in replication and are encoded by the remainder of the genome are NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5 (Qi et al. 2008). The recent advancements in understanding the structure and functions of these proteins are essential in potentially developing vaccines or antiviral drug therapies.
It is very important to thoroughly understand the complete steps of the Dengue life cycle because since there are no current therapies for the prevention or treatment of this illness, understanding each of the steps of the life cycle represents potential targets for antiviral drug discovery (Qi et al. 2008). The first step of the life cycle involves attachment of the viral receptor E protein to DC-SIGN ( dendritic-cell specific ICAM-grabbing non-integrin), GRP78/Bip (glucose-regulating protein 78), and CD-14 associated molecules which are some of the host cellular receptors that have been suggested as primary receptors for Dengue virus (Mukhopadhyay et al. 2005). Very little is known about the exact specifics of how a Flavivirus attaches to the receptors because it is difficult to culture a large amount of undamaged viral particles for cryo-electron microscopy studies (Qi et al. 2008). After the attachment of the virions, they gain entry into the host cell by receptor mediated endocytosis (Qi et al. 2008). Upon entry of the host cell the decrease in PH results in the acidification of the environment which causes the viral proteins to perform a conformational change of the E protein. After the virus uncoats, the C protein and the RNA separate, and the single stranded positive RNA strand is released into the cytoplasm and translation begins. Next, the RNA genome gets translated into one large polyprotein in order to make the polymerase. The protein is then cleaved by host and viral proteases. The RNA dependent RNA polymerase will create a complement of the Dengue virus genome which is a single stranded negative RNA. The negative strand will now serve as the template for the new single stranded RNA used in replication which takes place on the intracellular membranes. The next step which occurs after replication is completed is assembly and it takes place on the surface of the Endoplasmic Reticulum. The first virions to be assembled are immature, non infectious particles that contain an envelope made up of prM and E proteins, a nucleocapsid made up of C protein and the new genome, and a lipid layer. There are also other subviral particles that are assembled that lack a C protein and a genomic RNA. A mature virus will form after the cleavage of prM proteins by the host protease furin, and in the last step the mature virus particles are released by exocytosis from the host cell. Because the pathogenesis of Dengue is not completely understood, the cell tropism is also fairly unclear. Cell tropism describes the manner in which a virus evolves depending on the specific type of cell it targets. Scientist believe that the tropism of this virus involves viral virulence factors and host responses.
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Dengue which is responsible for the annual infection of 50 to 100 million people is a virus of
great concern because it accounts for the most deaths in the flavivirus genus (Qi et al. 2008).
Out of the large amount of infected people, roughly about 500,000 develop a more serious case
of Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS), which have very high
mortality rates (Mukhopadhyay et al. 2005). Dengue fever is characterized by a number of
symptoms that include fever, nausea, headache, rash, vomiting, myalgia, gastrointestinal
bleeding leucopenia, and severe pain in the joints. Dengue Hemorrhagic Fever is characterized
by four main symptoms: high fever, hemorrhagic phenomena, hepatomegaly, and circulatory
failure. The severity of this disease is determined by the plasma loss which can cause extreme
dehydration, high fever, and convulsions. Lastly, the Dengue Shock Syndrome which normally
results in death is characterized by circulatory failure, weak pulse, and ultimately a critical stage
of shock (World Health Organization). Although there is no conclusive evidence that shows any
long term consequences of the disease, in some cases people who suffer from neurological
damage will suffer from this the rest of their lives. The only long term consequence is that a
person develops immunity to the specific strain they were infected with.
The complete pathogenesis of this virus is not completely understood and still has substantial
gaps that require more research (Rico 2007). There are two theories that have been proposed to
explain the pathogenesis of DHF and DSS. The first theory focuses on the idea of antibody-
dependent enhancement and the second one is based on inherent dengue virus virulence.
Although there is evidence that supports both ideas, neither has been proven because of the lack
of adequate animal models (Chaudhry et al.2006). The Dengue virus exists in four related but
different viral serotypes which are Dengue 1-4 (Diallo et al. 1999). If an individual is infected
with one specific stereotype they produce antibodies specific only for that serotype. The antibody
dependent enhancement theory is the most popular theory and it states that an immune complex
will be formed from pre-existing non-neutralizing antibodies with the new virus serotype. This
results in an facilitation to infect macrophages and other Fc receptors (Qi et al. 2008).
Although currently there are no effective vaccines or anti-viral drug therapies for the treatment or the
prevention of Dengue virus infection, scientists are conducting studies to test potential future drug targets
(Qi et al. 2008). This therapeutic intervention is necessary because of the high mortality rate that is
associated with this disease. Understanding the life cycle of the Dengue virus is essential because it allows
scientist to discover new antiviral drugs that may target a specific life stage or protein (Qi et al. 2008).
Some of the current targets that are being studied are NS3 protein, NS3Pro activity, NS3 helicase activity,
RNA-dependent RNA polymerase, NS5 N-terminal methyltransferase GTP binding and E protein. Of all the
current targets, the E protein the RNA dependent RNA polymerase, and the NS3 helicase activity have
raised the most attention. The E protein is the most important target because it is found on the outer surface
of the virus and plays a crucial role in the attachment process. The E protein is involved with receptor
binding which is an essential step where the virus interacts with the host cell. If a target drug was developed
to block the binding of the E protein and the specific receptor this would be ideal for blocking the entry of
the Dengue Virus into the host cell. The only problem with this idea is that scientist have not been able to
prove specific flavivirus receptors. Another strong candidate for the development of antiviral drugs is the
RNA Dependent RNA polymerase. Because this enzyme is necessary for the replication of the virus, if we
could find a drug to disrupt RNA polymerase activity, we could then halt the process of viral genome
replication.As scientists learn more about the structure, proteins, enzymes and the replication process of
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Dengue virus, there are also future perspective drug targets for the potential drug treatment of the infection.
Some of the most promising targets for future research are inhibitors of virion assembly, capsid
dimerization, heterologous structural protein interactions, disruption of viral replication, and nonstructural
protein interaction (Geiss et al. 2009).
An effective vaccine also offers a good alternative for the prevention of this virus. Based on
previous knowledge of other Flavivirus vaccines that have been developed such as the yellow
fever vaccine scientists are trying to develop a new vaccine that will be as effective in fighting
off Dengue. (Geiss et al. 2009). Currently, the chimeric vaccine is the leading vaccine in clinical
trials. There are other vaccines under development that include live attenuated vaccines,
Inactivated vaccines, DNA, and viral vector vaccines (Webster et al. 2009). Creating a vaccine to
prevent this virus has been extremely difficult due to a lack of a suitable animal model.
Although we can test the vaccines' effectiveness on primate models, their pathological features
are completely different than a humans' which gives inaccurate results.
There are also some clinical approaches to alleviate the side effects of the infection, but the
treatment depends on the severity of the infection. A person who is diagnosed with Dengue
Hemorrhagic Fever will need to consume an oral rehydration solution or in more severe cases
hospitalization is needed for intravenous fluid therapy. With a diagnosis of Dengue Shock
Syndrome an immediate administration of intravenous fluid is needed but does not guarantee that
a person will survive (World Health Organization). The mortality rate for a person who receives
clinical treatment for DHS and DSS is 3% while a person who is untreated has a mortality rate of
50% (Price 2009).
The only current approach that is available for the prevention of the Dengue virus disease is the
control of the mosquito vector Aedes aegypti which is responsible for transmitting the disease
(World Health Organization). The other two approaches involve the development of effective
antiviral drugs and a vaccine which are both currently under development.
Dengue is a global public health issue because it is a major cause of morbidity causing more than
20,000 deaths per year and putting 2.5 billion people at risk (Qi et al. 2008). Although it
originated in primates in Africa centuries ago it independently found its way to humans. The
shift from monkeys to humans is estimated to have occurred between 100 to 800 years ago and
originally was not a major threat because it was contained to a small geographical area. Scientists
believe that World War II is what triggered the mass spread of the Aedes mosquitoes around the
world. The number of people infected with Dengue increased dramatically and the virus spread
to the Philippines, the Caribbean and South America. Today, Dengue is more prevalent than ever
and it is endemic in at least 100 countries ranging from Asia, to Africa, to the Caribbean and
South America (Center For Disease Control and Prevention). People who live in tropical and
subtropical areas are at higher risk for infection because this is where the Aedes mosquito
predominantly resides. Because the virus is spread though a mosquito that can travel almost
anywhere in the world, it is able to spread very quickly. The only current method of prevention
for the spread of this virus is the containment or the eradication of the Aedes aegypti mosquito.
An anti-viral drug or vaccine would be a more realistic approach but the development has been
very difficult. Similarly to any other disease, an outbreak of Dengue leads to social and
economical problems. An area that has a high number of Dengue infections can have a
tremendous economic impact on the population because when an epidemic occurs, the
community is shut down. The medical systems are also greatly affected because they are
overloaded with cases of DSS and DHF. When this happens international travel, restaurants,
tourism and businesses are also affected which slows down the economy.
The last pandemic of Dengue virus began in the 1950's and over the last 50 years it has
progressively been getting worse. This means we are in the midst of a major outbreak which
calls for immediate measures. Although all of the specifics of this virus are not completely
understood, continuous research is the key to finding preventable measures that could possibly
lead to the eradication of this fatal disease. As technology advances scientist also advance in
their discoveries. Until we find a cure for this global problem everyone could be at risk. Next
time a mosquito lands on your arm, think about all the people who have been in your same
situation but instead of a simple bump, it led to severe illness.
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