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Zika virus (ZIKV; species Orthoflavivirus zikaense) is an enveloped, positive-sense, single-stranded RNA virus of the genus Orthoflavivirus, family Flaviviridae. It causes Zika fever, congenital Zika syndrome, and a proportion of cases of Guillain–Barré syndrome. It is transmitted mainly by day-biting female Aedes mosquitoes, chiefly Aedes aegypti and Aedes albopictus, together with forest-dwelling African species. Unusually among mosquito-borne viruses, it also passes efficiently from person to person: across the placenta from mother to fetus, through sexual contact, and through blood transfusion.

First isolated in 1947 from a caged monkey in the Zika Forest of Uganda, the virus caused only scattered infections across Africa and Asia for six decades. From 2007, an Asian lineage spread through Micronesia, French Polynesia, and then the Americas, where between 2015 and 2017 it infected well over a million people across more than eighty countries and territories. Around four in five infections cause no symptoms, and most of the rest produce a mild illness with rash, conjunctivitis, and joint pain. Infection during pregnancy, however, allows the virus to cross the placenta and infect the cells that generate the fetal cerebral cortex, causing microcephaly and other severe brain damage.

The mature virus particle is unusually stable, retaining its structure and infectivity at temperatures around 40 °C that degrade related viruses. Replication inside the mosquito peaks near 29 °C. The range and seasonality of the virus are therefore closely tied to temperature, to El Niño, to urban warming, and to climate change.

Discovery in the Zika Forest and Taxonomic Placement

Zika virus was found in April 1947 during a study of forest yellow fever run by Alexander Haddow, George Dick, and colleagues at the Yellow Fever Research Institute in Entebbe, Uganda. To identify the mosquitoes and monkeys involved in yellow fever transmission, the researchers placed caged rhesus macaques on platforms in the canopy of the Zika Forest beside Lake Victoria; zika means "overgrown" in Luganda. One monkey, numbered 766, developed a fever, and inoculating mice with its serum yielded a new virus, the strain still known as MR 766. The virus was isolated again in January 1948 from wild Aedes africanus mosquitoes caught in the same forest. Serological studies confirmed human infections in Uganda, Tanzania, and Nigeria in the early 1950s.

The virus belongs to the genus Orthoflavivirus in the family Flaviviridae. Its closest relative is Spondweni virus; together they form a group distinct from those containing the four dengue virus types and from the group containing Japanese encephalitis virus and West Nile virus. Zika virus shares roughly 55 to 58% of its envelope protein sequence with dengue virus.

Divergence of the African and Asian Lineages

Unlike dengue virus, which exists as four types that do not cross-neutralize, all Zika strains belong to a single serotype: antibodies raised against one strain neutralize all others. Genome sequencing nevertheless divides the virus into two lineages, with the African one further subdivided, that differ markedly in behaviour.

The two lineages of Zika virus

Pacific and Pan-American Expansion and Epidemic Mutations

Molecular dating suggests the virus reached Southeast Asia from Africa at some point in the past few centuries, though estimates vary widely. It was first isolated in Asia from mosquitoes in Malaysia in 1966 and caused occasional human cases thereafter, probably often mistaken for mild dengue.

From 2007 the Asian lineage spread eastward across the Pacific:

1. Yap, Federated States of Micronesia (2007). The first recorded outbreak outside Africa and Asia. Serological surveys indicated that roughly three-quarters of the island's residents were infected within a few months, though only a minority had symptoms. Because the population was small, no cases of microcephaly or Guillain–Barré syndrome were detected.
2. French Polynesia (2013 to 2014). An estimated two-thirds of the population was infected. Forty-two cases of Guillain–Barré syndrome occurred, far above the usual rate, and a cluster of fetal brain malformations was identified retrospectively, giving the first indication that the virus damages the developing brain.
3. The Americas (2013 to 2017). Genome sequencing by Nuno Faria, Oliver Pybus, Kristian Andersen, and others showed that the virus reached northeastern Brazil by air travel around late 2013, more than a year before it was first confirmed clinically in May 2015. Helped by dense urban mosquito populations and the exceptionally warm El Niño of 2015 to 2016, it spread across South and Central America, the Caribbean, Mexico, and into Florida and Texas, and was exported to Cabo Verde, Angola, Singapore, and Thailand.

Comparing pre-epidemic Asian strains with epidemic ones identified four amino acid changes that may have contributed to the virus's new behaviour. Most of the evidence comes from engineered viruses tested in cells and mice, so the contribution of each change in human epidemics remains uncertain.

Amino acid changes associated with the epidemic lineage

Envelope Glycosylation at Asn154 and Thermal Stability

The mature particle is about 50 nm across. Structures solved in 2016 by Devika Sirohi, Richard Kuhn, Michael Rossmann, and colleagues, and independently by Shee-Mei Lok's group, showed the same overall arrangement as in dengue and West Nile viruses: 180 copies each of the envelope (E) and membrane (M) proteins lying flat against the lipid membrane as 90 pairs, grouped in threes into thirty flat rafts.

Each E protein folds into three domains, with the fusion loop at the tip of the second domain tucked against the partner protein in the pair. Two features distinguish Zika virus:

1. A single, prominent sugar group. Dengue E proteins carry two attached sugars, one of which binds the human receptor DC-SIGN. Zika lacks that site and carries only one, at asparagine 154 in the first domain. A five-residue insertion in the surrounding loop makes it project above the surface and reach across to sit over the partner protein's fusion loop. The sugar is required for the virus to cross the mosquito gut wall: laboratory strains that lost it during decades of passage in mice are no longer infectious to mosquitoes by feeding. It may also limit the access of cross-reactive dengue antibodies to the fusion loop beneath.
2. Unusual thermal stability. Dengue particles, particularly DENV-2, loosen and expand when warmed from mosquito to human body temperature, exposing the underlying membrane and losing infectivity within hours at 40 °C. Zika particles remain compact and infectious at that temperature, which has been attributed to a denser network of bonds between and within the protein pairs and a more tightly packed membrane anchor. The difference is one of degree and varies with strain and duration.

This stability is thought to underlie the virus's persistence in body fluids where dengue does not survive, including semen, urine, saliva, amniotic fluid, and breast milk, and so to enable sexual and congenital transmission.

Genomic Organization and Non-Coding sfRNA

The genome is a single RNA strand of about 10,800 bases, with a higher proportion of G and C than dengue virus. It carries a cap at one end and ends in a folded structure at the other, with no poly(A) tail.

A single reading frame encodes one long protein of about 3,400 amino acids, cut by host and viral enzymes into three structural proteins, the capsid, precursor membrane, and envelope, and seven non-structural proteins, NS1 to NS5. Short untranslated regions at either end carry the structures that allow the genome to circularize, which is necessary for the viral polymerase to copy it.

The region at the end of the genome folds into two knotted structures that stall the host enzyme that degrades RNA, leaving behind two abundant non-coding fragments. These bind a host protein needed to activate RNA sensing, suppressing interferon production. They have also been reported to sequester RNA-binding proteins in fetal brain cells and to interfere with the mosquito's RNA interference defences.

Attachment Receptors and Apoptotic Mimicry

Zika virus spreads by four routes: mosquito bites in both forest and urban cycles, transmission from mother to fetus, sexual transmission, and transfusion.

A feeding mosquito deposits virus into the skin, where it infects keratinocytes, fibroblasts, and immune cells before travelling via the lymph nodes into the bloodstream.

To enter the wide range of cells it infects, including those of the skin, placenta, testis, retina, and fetal brain, the virus uses three kinds of receptor before being taken up into the cell and fusing with the membrane of an acidified compartment:

• Lectins such as DC-SIGN bind the sugar group at asparagine 154.
• Phosphatidylserine receptors. Because the virus buds into the endoplasmic reticulum, its envelope carries phosphatidylserine, a lipid that cells normally display only when dying. Receptors that clear dying cells therefore bind the virus, either directly or through bridging proteins. The most studied is AXL, abundant on glial cells, blood vessel lining, and testicular Sertoli cells. Binding both draws the virus into the cell and switches on inhibitory proteins that shut down interferon signalling.
• Receptors on neural progenitors. Although AXL is abundant in the fetal brain, deleting it from laboratory-grown human progenitor cells does not prevent infection. In these cells the virus appears to use integrins and a neural adhesion molecule instead.

Maternal Viremia and Breaching the Placental Barrier

Maternal infection is often prolonged, with virus detectable for weeks rather than days, apparently because the infected placenta continues to release virus and because viral RNA persists bound to red blood cells.

Cohort studies in Brazil, Colombia, French Polynesia, and the United States indicate that infection in pregnancy leads to birth defects in roughly 5 to 10% of cases overall, with the highest risk, around 8 to 11%, following infection in the first trimester. Later infections carry lower risk of structural damage but can still cause developmental delay, eye damage, and white-matter injury.

The fetal tissues of the placenta are covered by a continuous layer, the syncytiotrophoblast, which has no gaps between cells and secretes antiviral proteins that make it resistant to infection. Three routes past this barrier have been proposed:

1. Early pregnancy vulnerability. Before this layer matures, the underlying cells and the maternal immune cells of the uterine lining carry the relevant receptors and have weak antiviral defences, allowing the virus to replicate through into the fetal tissue.
2. Damage by secreted NS1. Soluble NS1 released into the maternal blood binds placental and umbilical vessels and activates enzymes that strip their protective surface layer and loosen the junctions between cells.
3. Carriage across by antibodies. In placental explants and animal models, pre-existing dengue antibodies that bind Zika without neutralizing it can be carried across the barrier by the receptor that normally transports maternal antibodies to the fetus, taking the intact virus with them. Whether this contributes materially in human pregnancies is unresolved, since epidemiological studies have given mixed results.

Once in the fetal part of the placenta, the virus infects Hofbauer cells, the fetal macrophages there, replicating in them persistently without killing them and using them to reach the fetal circulation.

Radial Glial Progenitor Depletion and Congenital Zika Syndrome

Reaching the fetal brain, the virus selectively infects radial glial cells lining the ventricles. These cells are both the source of all cortical neurons and the scaffold along which new neurons migrate outward. Mature neurons are much less readily infected.

Mechanisms of damage to neural progenitor cells

The virus also infects microglia and astrocytes, which release inflammatory signals that damage neighbouring uninfected cells.

The resulting loss of cortical tissue produces the characteristic features of congenital Zika syndrome:

1. Severe microcephaly. Because the brain grows and then collapses after the progenitor layer is destroyed, the skull bones fold inward, producing overlapping sutures, a prominent occiput, and redundant folds of scalp skin.
2. Calcification and malformed cortex. Calcium deposits form at the junction between the thin cortex and the white matter beneath, a pattern that distinguishes the condition from congenital cytomegalovirus infection, which calcifies around the ventricles. The ventricles enlarge to fill the space, and the cortex is abnormally smooth or malformed, often with a small cerebellum and an absent or thin corpus callosum.
3. Eye damage, in roughly a third to a half of affected infants, including pigment changes and scarring of the macula, underdeveloped optic nerves, glaucoma, and cataract.
4. Fixed joint contractures, caused by loss of the motor neurons that drive fetal limb movement.
5. Later problems, including severe stiffness, difficulty swallowing, hearing loss, and epilepsy, which affects around half of children with the syndrome.

Testicular Immune Privilege and Sexual Transmission

Zika is the only mosquito-borne flavivirus established as a sexually transmitted infection. Most documented cases are from men to women, but transmission in the other direction and between men has also occurred.

Although virus is cleared from blood within one to two weeks, roughly half of infected men shed viral RNA in semen, typically for about five to six weeks, occasionally for many months. Infectious virus, as opposed to RNA, has been cultured for shorter periods, up to about two months after symptoms begin, and peak levels in semen can greatly exceed those in blood.

This persistence reflects the immune privilege of the testis. Sertoli cells, which form the barrier isolating developing sperm from the immune system, carry high levels of AXL and are infected without being killed. Viral proteins and inflammatory signals loosen the junctions between them, letting virus into the compartment beyond, where immune responses are suppressed. The virus infects developing sperm cells, hormone-producing cells, and the lining of the epididymis and prostate. Infected men show a temporary fall in sperm count and testosterone before recovering.

Pathogenesis of Zika-Associated Guillain–Barré Syndrome

In adults, the most serious complication is Guillain–Barré syndrome, an immune attack on peripheral nerves causing rapidly ascending weakness, loss of reflexes, facial weakness, and in a quarter to a third of patients, respiratory failure requiring ventilation.

Studies in French Polynesia, Colombia, and Brazil established an association. Estimates of risk vary; the French Polynesian outbreak gave roughly two cases per ten thousand infections, comparable to the risk after Campylobacter infection. Unlike classical cases, which begin weeks after an infection has resolved, Zika-associated cases typically begin within about a week of the first symptoms, while virus may still be detectable.

Three mechanisms have been proposed: resemblance between short stretches of viral protein and components of peripheral nerve; antibodies against nerve surface lipids, found in patient serum; and direct infection of Schwann cells, which carry AXL, breaking immune tolerance locally.

Bidirectional Immunological Cross-Reactivity With Dengue Virus

Because Zika and dengue viruses share much of their envelope sequence, including an almost identical fusion loop, and are spread by the same mosquito in the same places, infection with one shapes the response to the other.

Interactions between Zika and dengue immunity

Combined Vector-Borne and Sexual Reproduction Number

Because Zika spreads both through mosquitoes and directly between people, its dynamics require combining the standard vector-borne model with one for sexual transmission, as formulated by Gao, Ruan, Chowell, and colleagues.

For the mosquito route, the number of new human infections arising from one infected person through a complete cycle is:

where m is mosquitoes per person, a the biting rate, b and c the transmission probabilities, μ the mosquito death rate, n the time the virus needs to develop in the mosquito, and 1/_γ__v the few days a person is infectious to mosquitoes.

For the sexual route, R_0,sex depends on the transmission probability per partnership and on the much longer period of shedding in semen. Combining the two gives:

Two conclusions follow from fitting this to the 2015 to 2017 epidemics:

1. Sexual transmission alone cannot sustain an epidemic. Estimates of R_0,sex fall well below 1. Where mosquitoes are absent, an infected traveller can infect a partner, but the chain stops there.
2. Women of reproductive age are infected more often than men. Across outbreaks, symptomatic infection has been reported 50 to 90% more often in women aged 15 to 49 than in men of the same age. Sexual transmission and greater daytime indoor exposure have both been proposed as explanations, alongside differences in testing.

Temperature Thresholds and Herd Immunity Exhaustion

Experiments infecting Aedes aegypti across a range of constant temperatures, by Courtney Murdock, Erin Mordecai, Sadie Ryan, and colleagues, define the limits of transmission:

• Lower limit, 18.2 °C (95% confidence interval 16.5 to 20.5). This is warmer than for dengue. Dissections show why: at cool temperatures the virus infects the mosquito gut but cannot escape into the body cavity, and the time required exceeds the mosquito's lifespan.
• Optimum, 28.9 °C (28.2 to 29.6). Between 20 and 29 °C the time to infectiousness falls from more than three weeks to under ten days, while the mosquito bites more often and still lives long enough to transmit.
• Upper limit, 34.7 °C (34.1 to 35.8). The virus itself remains stable at these temperatures, but mosquito survival collapses.

1. Why the epidemic was so large. Climate modelling by Caminade, Turner, and colleagues attributed much of the explosive spread in South America to the coincidence of the virus's arrival with the exceptionally strong El Niño of 2015 to 2016. Temperatures across Brazil and Colombia reached record levels, moving cities toward the optimum for transmission, while drought in northeastern Brazil forced households to store water indoors, increasing mosquito numbers.
2. Why cases then collapsed. Reported Zika cases across the Americas fell by more than 95% after 2017, even as dengue, carried by the same mosquito, reached record levels. The explanation lies in the difference between one serotype and four. Dengue cycles indefinitely because immunity to one type does not prevent infection with another. Zika has a single serotype, and one infection confers lasting immunity. Seroprevalence surveys found that a large majority of the population in the worst-affected cities had been infected within two seasons, leaving too few susceptible people to sustain transmission.
3. Why it may return. Immunity does not disappear, but the susceptible population replenishes as children are born. Models suggest that susceptibility may be sufficient for renewed epidemics within one to three decades of the pandemic. Reintroduction could come from continuing circulation in Asia, where India and neighbouring countries have had urban outbreaks, or from forest cycles now established in Brazilian marmosets and capuchin monkeys. Separately, projections indicate that warming will extend the area suitable for transmission toward the poles and to higher elevations, bringing substantial additional populations into range by mid-century, though the figures depend heavily on the scenario assumed.

Multi-Fluid PCR and NS1 Blockade-of-Binding Serology

Diagnosis is complicated by two problems: the amount of virus in blood is lower and shorter-lived than for dengue, and antibodies against related viruses cross-react extensively, especially in people previously infected with dengue or vaccinated against yellow fever.

• Testing several sample types by PCR. Virus is usually detectable in blood only for the first week. It persists longer in urine, for two to three weeks, and longest in whole blood, where it remains bound to red cells for up to two or three months. In pregnant women carrying an infected fetus, low levels in blood can persist for many weeks.
• Antibody tests specific to Zika. Standard antibody tests cross-react with dengue. A test developed by Balmaseda, Harris, and colleagues instead measures whether a patient's serum blocks a monoclonal antibody from binding a Zika-specific site on NS1, and performs well even in people with several previous dengue infections. Neutralization tests remain the reference method.

Clinical Trial Vaccine Candidates and Human Challenge Models

No antiviral drug exists, and treatment is supportive, using paracetamol and avoiding aspirin and similar drugs until dengue has been excluded. Prevention therefore depends on a vaccine, which must meet three requirements: it must prevent maternal viraemia entirely, since even brief infection can damage a fetus; it must not generate antibodies that would worsen a later dengue infection; and for use in pregnancy, non-replicating platforms are preferred.

Vaccine candidates in clinical trials

Because transmission collapsed after 2017, there is too little natural infection to run conventional efficacy trials. Researchers led by Anna Durbin and Stephen Whitehead have therefore developed a model in which healthy non-pregnant volunteers are deliberately infected with a low dose under close supervision, with the aim of testing candidate vaccines directly. The model is still being validated.

Engineered Monoclonal Antibodies and Mosquito Control

Potent antibodies isolated from recovered patients bind across the envelope protein pair and prevent the virus from fusing with host membranes. For use in pregnancy, these are engineered in two ways: mutations that abolish binding to the receptors involved in antibody-dependent enhancement, so that they cannot worsen a Zika or dengue infection, and mutations that extend their lifetime in the blood while preserving transport across the placenta.

Travellers returning from affected areas are advised to use barrier contraception for some months, reflecting persistence in semen. Mosquito control uses the same methods as for dengue:

• Wolbachia. Introducing this bacterium into Aedes aegypti greatly reduces the amount of Zika virus reaching mosquito saliva, with laboratory feeding experiments showing reductions of well over 90% and in some cases no detectable transmission. Deployments against dengue in Brazil and elsewhere are expected to reduce Zika transmission as well.
• Genetic and targeted methods. Releases of mosquitoes engineered so that female offspring die, sterile-male techniques, and spraying the indoor surfaces where the mosquitoes actually rest, combined with larvicides and traps that spread an insect growth regulator between breeding sites.

• Zika fever
• Congenital Zika syndrome
• Aedes aegypti
• Dengue virus
• Flaviviridae

Why is Zika virus thermally stable at 40 °C compared to dengue virus?

Cryo-electron microscopy structures demonstrate that the Zika virus envelope (E) glycoprotein shell contains a tighter network of hydrogen bonds and hydrophobic interactions across E-E dimer interfaces and transmembrane helices, alongside an extended 150-loop carrying the Asn154 glycan that caps the partner monomer's fusion loop. Consequently, Zika virions remain structurally compact and infectious at 40 °C, whereas dengue virions undergo conformational expansion ("breathing") and lose infectivity rapidly, enabling Zika to persist in semen, urine, and amniotic fluid.

How does Zika virus cause microcephaly in the developing fetal brain?

After crossing the placental barrier and infecting fetal Hofbauer macrophages, Zika virus selectively infects ventricular radial glial neural progenitor cells. Inside radial glia, viral NS4A and NS4B inhibit Akt–mTOR signaling to halt neurogenesis, NS2A degrades adherens-junction proteins, NS3/NS5 disrupt mitotic centrosomes, and 3′ UTR non-coding sfRNA sequesters the neural RNA-binding protein Musashi-1, triggering cell-cycle arrest and apoptosis of cortical progenitors.

Why did Zika virus cases drop sharply after 2017 while dengue continued to rise?

Unlike dengue virus, which circulates as four antigenically distinct serotypes that allow sequential infections, all Zika virus lineages belong to a single serotype that elicits lifelong homotypic neutralizing immunity after a single exposure. Because the 2015–2017 Pan-American epidemic infected 50–70% of residents in high-transmission urban centers, population herd immunity rapidly exceeded the critical threshold (1 − 1/_R_₀ ≈ 67%), exhausting susceptible hosts until demographic birth cohorts replenish susceptibility.