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Zika fever is known since 1947 when it was discovered in a rhesus monkey in Uganda [1]. Five years later cases of the fever were registered in humans in Uganda and Tanzania, subsequently, outbreaks occurred not only in Africa but in Asia as well. Zika virus attracted increased attention in spring 2015, when a new outbreak, first registered in Brazil, spilled over the whole Southern America and travellers carried the disease to US and Europe. The geography of the outbreaks is associated with a high prevalence of microcephaly in newborns and increased number of the Guillain—Barré syndrome cases in the same regions. Most of the mothers whose children died of microcephaly within 20 hours after birth had fever symptoms during the first or the second trimester of pregnancy. Since January 2014 the cases of the fever were registered in 33 countries. There are no vaccines or medication available against Zika at this moment. On February 1st 2016 the World Health Organization declared Zika fever an international health emergency [2-4].

The virus outbreak, concomitant diseases and treatment

Zika virus belongs to the same systematic group, Flaviviridae, as the hepatitis C, Dengue, yellow fever and West Nile. Yellow fever and Dengue together take up to 50000 lives per year and the number of infected people is reaching hundred thousand or even hundred million per year, respectively [5; 6]. Zika virus is not as deadly, however, more than one and a half million people were infected since the beginning of the current outbreak [4].

Zika symptoms are similar to the symptoms of Dengue in a mild form: fever, rash, muscle and joint pain, headache and conjunctivitis [7]. Symptoms stay from two to seven days, however, in most cases, there are no symptoms at all. The link between Zika infection in pregnant women and under development of the head tissue in newborns is not yet fully proven but is supported by indirect evidence: prior to outbreak onset, the number of babies with microcephaly was 1-2 per 10000, now the proportion is 10 times higher in the regions of the outbreak. In single microcephaly cases, Zika virions were found in the brain tissues of the embryo [8]. The exact mechanisms of virus interference with head development are still unknown.

The link between Zika fever and Guillain—Barré syndrome is not yet proven either, however, the number of Guillain—Barré cases is also elevated in the regions affected by Zika. Guillain—Barré syndrome is an autoimmune disease in which immune cells attack the nerve cells within the body, bringing muscle weakness and paralysis. The symptoms can last for several weeks or even 2-3 months [9].

Tropical fevers are very common in the regions of Africa, Asia and America with large populations of mosquitoes of the Aedes genus, who act as the disease vectors. Currently active Zika virus could have migrated from Africa and Asia to the South America across Micronesia and French Polynesia, where the outbreak of the virus took place in 2013. After that, the virus spread in Brazil during the World Cup in 2014 [10]. The abundance of Zika and related fevers can grow due to the global climate change and expand of the mosquitoes habitat [11 — 13]. Zika virus can also be transmitted directly between humans via sexual intercourse, however, this way of transmission is rare and the main route of the disease transmission is still through mosquito bites [14].

By the most optimistic prediction the first Zika vaccine could become available no earlier than the end of the 2016 [15].

Virus structure

The virion of flaviviruses has a diameter of 50 nm, which is approximately two and a half times less than the diameters of HIV or influenza viruses. The viral particle includes three types of proteins: E, M and C. Surface proteins E and M form a regular spherical shell and allow the virus to enter the cell during infection. Several domains of the surface proteins are integrated into the lipid membrane which is taken by the virus from the endoplasmic reticulum of the host cell. The major surface protein E is glycosylated (in the model — dark grey spots on the surface of the virion) [16].

The genome of the virus is represented by the single RNA strand bound to the capsid proteins. It is thought that the capsid of flaviviruses is disordered and does not form regular structures [17; 18]. The RNA tends to concentrate around C-protein dimers [19]. Once in the cell, the RNA can readily become a matrix for protein synthesis (the positive-sense RNA). Apart from the structural proteins C, E and M, flaviviruses genome encodes seven proteins not present in the viral particle. These non-structural proteins coordinate viral replication and inhibit immune response [20]. In the Zika model all the virus-encoded proteins are shown in the shades of blue and green, and the components taken from the cell are shown in grey.

In the human body Zika viral particles infect dendritic cells and then are carried to other tissues with the blood flow [21]. The virus is capable of entering skin cells (keratinocytes of epidermis and dermal fibroblasts). The cell receptor for the Zika virion is not yet identified but researchers highlight the AXL surface protein among a couple of dozens of candidates [22].

Due to that fact that the data regarding Zika structure is very limited, the model was created based on the published information about the structure of related viruses of yellow fever, West Nile and Dengue. Computational biologists from the scientific modeling department of Visual Science used methods of structural bioinformatics to predict the possible structures of Zika proteins. These methods are widely used not only in fundamental research but also in drug development and molecular interaction studies.

The model of Zika virus is a part of the non-commercial educational project Viral Park, which was launched by the Visual Science in 2009. The project includes models of HIV, influenza A/H1N1, adenovirus, Ebola and papilloma viruses. Models and visualizations of the Viral Park received Science Magazine and National Science Foundation awards, appeared on the cover of Nature Medicine special issue, were published in the NY Times, Vaccines textbook, Cell journal Picture Show and were included into presentations of the Nobel Prize winners. The Viral Park models are made in atomic resolution, and are built based on the latest scientific data and computational biology simulations. The models sum up all the available information about the structure of the most widespread and dangerous human viruses and may act as a stand-alone scientific reviews in a graphical form.

  • Project author and supervisor, 3D-visualizator and technologist:
    Ivan Konstantinov
  • Science consultant, texts author, 3D-modeler assistant:
    Yury Stefanov, PhD
  • Head molecular modeler:
    Anastasia Bakulina, PhD, Novosibirsk State University
  • Molecular modeler:
    Dmitri Scherbinin, PhD
  • 3D-modeler:
    Alex Kovalevsky
  • Web-technologists:
    Kirill Grishanin, Gleb Kondratenko
  • Corrector:
    Anna Voznesenskaya

We are grateful to Dr. Ronald Harty for useful comments and providing important information.

We also want to thank Dmitry Barbanel and Amy Gordon for their help in the preparation of the poster.

Molecular modelling through computer graphics permits plenty of latitude for exercising artistic talent to inform, explain and instruct. Visual Science shows the way with its high quality, accurate, informative graphics that explain even the most complex processes of life.
Lewis Sadler MA, Msc.
Chief Science Officer at Visible Productions Inc., Research Assistant Prof. University of Illinois at Chicago, (US)