Zika virus

This article is about the virus. For the disease, see Zika fever. For the current outbreak, see Zika virus outbreak (2015–present).

Zika virus
Electron micrograph of the virus. Virus particles are 40 nm in diameter, with an outer envelope and a dense inner core.[1]
Zika virus capsid model, colored by chains, PDB entry 5ire.[2]
Virus classification
Group: Group IV ((+)ssRNA)
Family: Flaviviridae
Genus: Flavivirus
Species: Zika virus

Zika virus /ˈziːkə, ˈzɪkə/[3][4] (ZIKV) is a member of the virus family Flaviviridae and the genus Flavivirus.[5] It is spread by daytime-active Aedes mosquitoes, such as A. aegypti and A. albopictus.[5] Its name comes from the Zika Forest of Uganda, where the virus was first isolated in 1947.[6] Zika virus is related to dengue, yellow fever, Japanese encephalitis, and West Nile viruses.[6]

The infection, known as Zika fever, often causes no or only mild symptoms, similar to a mild form of dengue fever.[5] It is treated by rest.[7] Since the 1950s, it has been known to occur within a narrow equatorial belt from Africa to Asia. The virus spread eastward across the Pacific Ocean 2013–2014 Zika virus outbreaks in Oceania to French Polynesia, New Caledonia, the Cook Islands, and Easter Island, and in 2015 to Mexico, Central America, the Caribbean, and South America, where the Zika outbreak has reached pandemic levels.[8] As of 2016, the illness cannot be prevented by medications or vaccines.[7] Zika may spread from a pregnant woman to the baby. This may result in microcephaly and other severe brain problems.[9][10] Zika infections in adults can result in Guillain-Barré syndrome.[11]

In January 2016, the United States Centers for Disease Control and Prevention (CDC) issued travel guidance on affected countries, including the use of enhanced precautions, and guidelines for pregnant women including considering postponing travel.[12][13] Other governments or health agencies also issued similar travel warnings,[14][15][16] while Colombia, the Dominican Republic, Ecuador, El Salvador, and Jamaica advised women to postpone getting pregnant until more is known about the risks.[15][17]

Virology

A video explanation of the Zika virus and of Zika fever

The Zika virus belongs to Flaviviridae and the genus Flavivirus, and is thus related to the dengue, yellow fever, Japanese encephalitis, and West Nile viruses. Like other flaviviruses, Zika virus is enveloped and icosahedral and has a nonsegmented, single-stranded, positive-sense RNA genome. It is most closely related to the Spondweni virus and is one of the two viruses in the Spondweni virus clade.[18][19]

A positive-sense RNA genome can be directly translated into viral proteins. In other flaviviruses, such as the similarly sized West Nile virus, the RNA genome genes encode seven nonstructural proteins and three structural proteins. The structural proteins encapsulate the virus. The replicated RNA strand is held within a nucleocapsid formed from 12-kDa protein blocks; the capsid is contained within a host-derived membrane modified with two viral glycoproteins. Replication of the viral genome would first require creation of an anti-sense nucleotide strand.

There are two lineages of Zika: the African lineage, and the Asian lineage.[20] Phylogenetic studies indicate that the virus spreading in the Americas is most closely related to the Asian strain, which circulated in French Polynesia during the 2013–2014 outbreak.[20][21] The complete genome sequence of the Zika has been published.[22] Western Hemisphere Zika is found to be 89% identical to African genotypes, but is most closely related to the strain found in French Polynesia during 2013–2014.[23]

Transmission

The vertebrate hosts of the virus were primarily monkeys in a so-called enzootic mosquito-monkey-mosquito cycle, with only occasional transmission to humans. Before the current pandemic began in 2007, Zika "rarely caused recognized 'spillover' infections in humans, even in highly enzootic areas". Infrequently, other arboviruses have become established as a human disease though, and spread in a mosquito–human–mosquito cycle, like the yellow fever virus and the dengue fever virus (both flaviruses), and the chikungunya virus (a togavirus).[24]

Mosquito

Aedes aegypti predicted distribution
Global Aedes aegypti predicted distribution. The map depicts the probability of occurrence (blue=none, red=highest occurrence).

Zika is primarily spread by the female Aedes aegypti mosquito which is active mostly in the daytime. The mosquitos must feed on blood in order to lay eggs.[25]:2 The virus has also been isolated from a number of arboreal mosquito species in the Aedes genus, such as A. africanus, A. apicoargenteus, A. furcifer, A. hensilli, A. luteocephalus and A. vittatus, with an extrinsic incubation period in mosquitoes of about 10 days.[26]

The true extent of the vectors is still unknown. Zika has been detected in many more species of Aedes, along with Anopheles coustani, Mansonia uniformis, and Culex perfuscus, although this alone does not incriminate them as a vector.[27]

Transmission by A. albopictus, the tiger mosquito, was reported from a 2007 urban outbreak in Gabon where it had newly invaded the country and become the primary vector for the concomitant chikungunya and dengue virus outbreaks.[28] There is concern for autochthonous infections in urban areas of European countries infested by A. albopictus because the first two cases of laboratory confirmed Zika infections imported into Italy were reported from viremic travelers returning from French Polynesia.[29]

The potential societal risk of Zika can be delimited by the distribution of the mosquito species that transmit it. The global distribution of the most cited carrier of Zika, A. aegypti, is expanding due to global trade and travel.[30] A. aegypti distribution is now the most extensive ever recorded – across all continents including North America and even the European periphery (Madeira, the Netherlands, and the northeastern Black Sea coast).[31] A mosquito population capable of carrying Zika has been found in a Capitol Hill neighborhood of Washington, D. C., and genetic evidence suggests they survived at least four consecutive winters in the region. The study authors conclude that mosquitos are adapting for persistence in a northern climate.[32]

Since 2015, news reports have drawn attention to the spread of Zika in Latin America and the Caribbean.[33] The countries and territories that have been identified by the Pan American Health Organisation as having experienced "local Zika virus transmission" are Barbados, Bolivia, Brazil, Colombia, the Dominican Republic, Ecuador, El Salvador, French Guiana, Guadeloupe, Guatemala, Guyana, Haiti, Honduras, Martinique, Mexico, Panama, Paraguay, Puerto Rico, Saint Martin, Suriname, and Venezuela.[34][35][36]

Sexual

Zika can be transmitted from a man to his sex partners.[37] As of April 2016 sexual transmission of Zika has been documented in six countries – Argentina, Chile, France, Italy, New Zealand and the United States – during the 2015 outbreak.[11]

In 2014, Zika capable of growth in lab culture was found in the semen of a man at least two weeks (and possibly up to 10 weeks) after he fell ill with Zika fever.[38][39] The second report is of a United States biologist who had been bitten many times while studying mosquitoes in Senegal. Six days after returning home in August 2008, he fell ill with symptoms of Zika fever but not before having unprotected intercourse with his wife, who had not been outside the US in 2008. She subsequently developed symptoms of Zika fever, and Zika antibodies in both the biologist's and his wife's blood confirmed the diagnosis.[38][40] In the third case, in early February 2016 the Dallas County Health and Human Services department reported that a person contracted Zika fever after sexual contact with an ill person who had recently returned from a high risk country. This case is still under investigation.[38][41] As of February 2016 fourteen additional cases of possible sexual transmission have been under investigation. All cases involve transmitting the Zika from men to women and it is unknown whether women can transmit Zika to their sexual partners.[42]

As of March 2016, the CDC updated its recommendations about length of precautions for couples and advised that couples with men who have confirmed Zika fever or symptoms of Zika should consider using condoms or not having sex (i.e., vaginal intercourse, anal intercourse, or fellatio) for at least 6 months after symptoms begin. This includes men who live in and men who traveled to areas with Zika. Couples with men who traveled to an area with Zika, but did not develop symptoms of Zika, should consider using condoms or not having sex for at least 8 weeks after their return in order to minimize risk. Couples with men who live in an area with Zika, but have not developed symptoms, might consider using condoms or not having sex while there is active Zika transmission in the area.[43]

The "incidence and duration of shedding in the male genitourinary tract is limited to one case report" and "testing of men for the purpose of assessing risk for sexual transmission is not recommended."[38]

Pregnancy

The Zika virus can spread from an infected mother to her fetus during pregnancy or at delivery.[44]

Blood transfusion

As of April 2016, two cases of Zika transmission through blood transfusions have been reported globally, both from Brazil,[45] after which the US Food and Drug Administration recommended screening blood donors and deferring high-risk donors for 4 weeks.[46][47] A potential risk had been suspected based on a blood-donor screening study during the French Polynesian Zika outbreak, in which 2.8% (42) of donors from November 2013 and February 2014 tested positive for Zika RNA and were all asymptomatic at the time of blood donation. Eleven of the positive donors reported symptoms of Zika fever after their donation, but only three of 34 samples grew in culture.[48]

Pathogenesis

Zika replicates in the mosquito's midgut epithelial cells and then its salivary gland cells. After 5–10 days, ZIKV can be found in the mosquito’s saliva which can then infect human. If the mosquito’s saliva is inoculated into human skin, the virus infect epidermal keratinocytes, skin fibroblasts in the skin and the Langerhans cells. The pathogenesis of the virus is hypothesized to continue with a spread to lymph nodes and the bloodstream.,[18][49] Flaviviruses generally replicate in the cytoplasm, but Zika antigens have been found in infected cell nuclei.[50]

Zika fever

Main article: Zika fever
Rash on an arm due to Zika

Common symptoms of infection with the virus include mild headaches, maculopapular rash, fever, malaise, conjunctivitis, and joint pains. Three well-documented cases of Zika were described in brief in 1954, whereas a detailed description was published in 1964; it began with a mild headache, and progressed to a maculopapular rash, fever, and back pain. Within two days, the rash started fading, and within three days, the fever resolved and only the rash remained. Thus far, Zika fever has been a relatively mild disease of limited scope, with only one in five persons developing symptoms, with no fatalities, but its true potential as a viral agent of disease is unknown.[26]

As of 2016, no vaccine or preventative drug is available. Symptoms can be treated with rest, fluids, and paracetamol (acetaminophen), while aspirin and other nonsteroidal anti-inflammatory drugs should be used only when dengue has been ruled out to reduce the risk of bleeding.[51]

Zika causes microcephaly and other severe brain anomalies in infants born of women infected with the virus. As of April 2016, the full range of birth defects caused by maternal infection was not known, nor was it understood whether the stage of pregnancy at which the mother became infected affects the fetus, nor if other risk factors might exist that affect outcomes.[9][10]

Vaccine development

Effective vaccines exist for several viruses of the flaviviridae family, namely Yellow fever vaccine, Japanese encephalitis vaccine, and Tick-borne encephalitis vaccine since the 1930s, and dengue fever vaccine since the mid-2010s.[52][53][54] WHO experts have suggested that the priority should be to develop inactivated vaccines and other non-live vaccines, which are safe to use in pregnant women and those of childbearing age.[55]

The NIH Vaccine Research Center (U.S.) began work towards developing a vaccine for Zika per a January 2016 report.[56] Bharat Biotech International (India) reported in early February 2016, that it was working on vaccines for Zika[57] using two approaches: "recombinant", involving genetic engineering, and "inactivated", where the virus is incapable of reproducing itself but can still trigger an immune response with animal trials of the inactivated version to commence in late February.[58] As of March 2016, 18 companies and institutions internationally were developing vaccines against Zika, but none had yet reached clinical trials.[55] Nikos Vasilakis of the UTMB predicted that it may take two years to develop a vaccine, but ten to twelve years may be needed before an effective Zika vaccine is approved by regulators for public use.[59]

History

Countries that have past or current evidence of Zika transmission (as of January 2016)[60]
Spread of Zika[23][61][62]
Spread of Zika in Africa and Asia, based on molecular sequence data

Virus isolation in monkeys and mosquitoes, 1947

The virus was first isolated in April 1947 from a rhesus macaque monkey that had been placed in a cage in the Zika Forest of Uganda, near Lake Victoria, by the scientists of the Yellow Fever Research Institute.[63] A second isolation from the mosquito A. africanus followed at the same site in January 1948.[64] When the monkey developed a fever, researchers isolated from its serum a "filterable transmissible agent" that was named Zika in 1948.[26][65]

First evidence of human infection, 1952

Zika had been known to infect humans from the results of serological surveys in Uganda and Nigeria, published in 1952: Among 84 people of all ages, 50 individuals had antibodies to Zika, and all above 40 years of age were immune.[66] A 1952 research study conducted in India had shown a "significant number" of Indians tested for Zika had exhibited an immune response to the virus, suggesting it had long been widespread within human populations.[67]

It was not until 1954 that the isolation of Zika from a human was published. This came as part of a 1952 outbreak investigation of jaundice suspected to be yellow fever. It was found in the blood of a 10-year-old Nigerian female with low-grade fever, headache, and evidence of malaria, but no jaundice, who recovered within three days. Blood was injected into the brain of laboratory mice, followed by up to 15 mice passages. The virus from mouse brains was then tested in neutralization tests using rhesus monkey sera specifically immune to Zika. In contrast, no virus was isolated from the blood of two infected adults with fever, jaundice, cough, diffuse joint pains in one and fever, headache, pain behind the eyes and in the joints. Infection was proven by a rise in Zika-specific serum antibodies.[66]

Spread in equatorial Africa and to Asia, 1951–1983

From 1951 through 1983, evidence of human infection with Zika was reported from other African countries, such as the Central African Republic, Egypt, Gabon, Sierra Leone, Tanzania, and Uganda, as well as in parts of Asia including India, Indonesia, Malaysia, the Philippines, Thailand, Vietnam and Pakistan.[26][68] From its discovery until 2007, there were only 14 confirmed human cases of Zika infection from Africa and Southeast Asia.[69]

Micronesia, 2007

In April 2007, the first outbreak outside of Africa and Asia occurred on the island of Yap in the Federated States of Micronesia, characterized by rash, conjunctivitis, and arthralgia, which was initially thought to be dengue, chikungunya, or Ross River disease.[70] Serum samples from patients in the acute phase of illness contained RNA of Zika. There were 49 confirmed cases, 59 unconfirmed cases, no hospitalizations, and no deaths.[71]

2013–2014

Oceania

Between 2013 and 2014, further epidemics occurred in French Polynesia, Easter Island, the Cook Islands, and New Caledonia.[4]

Other cases

On 22 March 2016 Reuters reported that Zika was isolated from a 2014 blood sample of an elderly man in Chittagong in Bangladesh as part of a retrospective study.[72]

Americas, 2015–present

As of early 2016, a widespread outbreak of Zika was ongoing, primarily in the Americas. The outbreak began in April 2015 in Brazil, and has spread to other countries in South America, Central America, Mexico, and the Caribbean. In January 2016, the WHO said the virus was likely to spread throughout most of the Americas by the end of the year;[73] and in February 2016, the WHO declared the cluster of microcephaly and Guillain–Barré syndrome cases reported in Brazil – strongly suspected to be associated with the Zika outbreak – a Public Health Emergency of International Concern.[6][74][75][76] It is estimated that 1.5 million people have been infected by Zika in Brazil,[77] with over 3,500 cases of microcephaly reported between October 2015 and January 2016.[78]

A number of countries have issued travel warnings, and the outbreak is expected to significantly impact the tourism industry.[6][79] Several countries have taken the unusual step of advising their citizens to delay pregnancy until more is known about the virus and its impact on fetal development.[17]

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