Virus Origins Of Henipavirus And Dengue Virus Biology Essay


Human beings were definitely not the first victims of viruses through time, but human beings are the ones who tried to investigate viruses' origins and applications. Constant research since 19th century revealed many different aspects of the viruses, there mechanisms, and of course different types of them. Thus, the database created from studying the viruses led to the term "Emerging Viruses". If we just analyze the word "emerge" we can extract the meaning of something that happens unexpectedly, and most of the times rapidly. Therefore the need to continuously gain knowledge about viruses is crucial, since this is the only way to create strategies to deal with them and of course ways of treatment (Drugs, Vaccines etc.). In order to avoid misfortunes from viruses, every one of us should have general knowledge for viruses, or governmental and private health services should provide information to keep everyone alert. Currently there is a vast amount of information concerning viruses that exists in literature both as a hard copy but also in electronic form (Databases available both online and in Universities' Libraries).

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Throughout this literature review we will concentrate on the general subject of emerging viruses, and further focus on two specific viruses (Henipavirus and Dengue Virus) just to reveal the significance of research, regarding the simultaneous support in ways of treatment, and the amount of information that can derive from it.


Hendra virus (HeV) and Nipah virus (NiV) two linked viruses of the paroxyviridae family, and belong to the genus Henipavirus which has only recently emerged. Both viruses can cause significant illness or even lead to death to humans and some other mammals. HeV seems that was the reason for an outbreak of acute respiratory disease in humans and thoroughbred horses in Brisbane, Australia in 1994 (Murray et al., 1995). HeV has emerged several times since it first appeared, having the last incidence in humans in July 2008. On that year there was 1 death report resulting from HeV. (Sun, 2008). NiV infection was detected for the first time in 1998 in Malaysia, affecting both pigs and humans (Chua et al., 2000). The fruit bat (Pteropus species) was the one playing the role of a reservoir for these viruses. Despite the fact that during their first outbreak, HeV and NiV isolated from humans and fruit bats were similar or identical, (Halpin et al.,1999) isolated NiV from different Asian countries showed larger differences (Harcourt et al., 2005).

Variation among human death rates appeared in the studies indicating 40% in Malaysia, 75% in Bangladesh and India, having also outbreaks that were associated with human to human transmission (Gurley et al., 2007). Bexause of the big number of pteropus fruit bats in Australia, southeast Asia, India and Africa, there is a continuous fear that Henipavirus will manage and cross the species barrier to infect new hosts and cause another outbreak. Regarding the progression path that the virus follows, data founded in the literature seem to be insufficient. Three fatal human cases out of 6 infections overall reported so far, all deriving from HeV (O'Sullivan et al., 1997; Selvey et al., 1995; Wong et al., in press). The patients that died from the virus developed a respiratory disease and pathological analysis showing gross lesions of congestion, haemorrhage and oedema of lungs, associated with alveolitis with syncytia (Selvey et al., 1995) as well as acute encephalitis (Wong et al., in press). Development of a lethal relapsing encephalitis about 1 year after the primary infection, characterized by leptomeningitis, necrosis and inflammation in different parts of the brain parenchyma was also reported (O'Sullivan et al., 1997; Sun, 2008)

Mechanism of infection:

Identified Paramyxoviruses

To enter the cells of the host, paramyxoviruses have to follow a specific order: viral attachment to the target cell, followed by fusion of the viral membrane to a host cell membrane [6]. Two key viral glycoproteins endorse these events to take place: the attachment protein helps for primary receptor binding of the virus to the target cell. In the meantime the F protein advances the membrane fusion events that are about to follow. The cell surface in a neutral pH environment seems to host both events. Interactions of the F protein and the homotypic attachment protein are suppose to control the start point of the fusion process for most paramyxoviruses. By the time that fusion reaction begins, a series of conformational changes in the F protein that first lead to insertion of a hydrophobic region into the target membrane seem to promote it, forming a protein bridge between the two membranes. Other conformational changes lead to formation of a helical bundle.

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Additional studies revealed that EphrinB2 acts as the receptor for the Hendra and Nipah viruses [8,9], having also EphrinB3 as an additional receptor for both viruses. Structural analysis of Nipah G presented alone or in complex with Ephrin B3 having little conformational change upon receptor binding, implying that only slight alterations in the attachment protein are enough to lead to the activation of the protein F [10]. EphrinB2 and B3 are used as ligands for a receptor family called Eph tyrosine. Expression of them in neurons, arterial endothelial cells, and smooth muscle is connected with the tissue distribution observed during Hendra and Nipah infection [3]. EphrinB2 and B3 are highly conserved between species. A large number of species seems to be infected by these pathogens. EphrinB2 and B3 deriving from horse, human, dog, pig, cat, and bat, serve as functional receptors for Hendra and Nipah. This reveals that the conserved expression of this receptor has an important role in the broad host range of these pathogens.

The Hendra and Nipah virus F proteins are originally synthesized as a precursor that must be proteolytically processed to two subunits (F1 and F2) to be fusogenically active (Figure 2A). For the majority of F proteins, this critical proteolytic processing event is promoted by furin, a cellular protease present primarily in the trans-Golgi network. It is very important to mention that the mechanism for proteolytic activation of the henipavirus F proteins is completely novel. Furin is not involved, since there is no furin consensus at the cleavage site, thus furin inhibitors have no effect on henipavirus F processing. Inhibitors or shRNA knock downs of cathepsin L (a cellular endosomal protease), seem to inhibit cleavage of the Hendra and Nipah F proteins. In vitro studies established proteolytic cleavage of the henipavirus F proteins at a single specific site by purified cathepsin L [6,12]. To enable this essential interaction with cathepsin L, endocytosis of the Hendra F protein [13] and the Nipah F protein [14] must occur. Then a re-trafficking event follows to the cell surface after proteolytic processing (Figure 2B). Once F protein is cleaved it found inside the packaged virion [3]. Fusion protein interactions which are needed for fusion, take place only after the protein F endocytic trafficking and proteolytic cleavage [15]. This automatically points out that the Hendra G attachment protein does not follow the complicated trafficking pathway mentioned before.

Clinical and experimental data show that multiple organ systems are affected, with the lungs and brain being the main sites that the virus replicates. For both viruses, acute and late-onset encephalitis has been clinically documented. The initial sites and duration of henipavirus replication upon infection are largely unknown, mostly because of the problem of having extensive in vivo experiments. As a result, the best possible target and time frame for drug intervention are not yet known. In theory though, therapeutics that targets the mucosa should reduce viral loads in the lung. Intravenous agents should decrease viral loads and reduce systemic spread. Despite the fact that is difficult to target the Central Nervous System (CNS), an important reduction in viral loads peripherally could give the ability to the host to generate a protective immune response.

Ways of Treatment:

Antiviral Drugs:

Until today only one antiviral drug has been used against henipaviruses and it was synthesized in 1972.

Vaccine Development:

Even though new reverse genetics systems have been developed for NiV [58], it is improbable that a live-attenuated vaccine will be approved for any BSL4 virus including HeV and NiV.


While the neutralizing antibodies brought out by a vaccine can be highly effective, purified neutralizing antibodies administered passively to acutely infected individuals can be as much efficient as the neutralizing antibodies brought out by a vaccine. Passive antibody therapy is routinely used for prophylaxis against several important human pathogens including hepatitis B, varicella, RSV and rabies virus.

Fusion Inhibitory Peptides:

Peptide sequences resulting from F glycoprotein HR domains of several paramyxoviruses, including HeV and NiV have been shown to be potent inhibitors of fusion [88-93]. Furthermore, HeV and NiV F glycoprotein HR domains have been shown to interact with each other and form the typical 6-helix coiled-coil bundles [94].

Soluble Receptor Molecules:

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A soluble virus receptor which binds G and prevents attachment of the virion to the host cell may also represent a feasible therapeutic strategy. It has been demonstrated that soluble ephrin-B2 ligands can block infectious henipavirus in vitro [27] and more recently, it has been confirmed that soluble ephrin-B2 ligands could block both ephrin-B2 and ephrin-B3 ligands mediated Henipavirus infections in vitro (Bossart, K. and Wang, L.; unpublished data).