Zika virus

Zika virus is an Orthoflavivirus transmitted mainly by Aedes mosquitoes that was an obscure cause of mild febrile illness for almost seventy years before erupting across the Pacific and the Americas in a 2015 to 2016 epidemic. That epidemic revealed two features that set Zika apart from the other arboviruses: it can be transmitted sexually and from mother to fetus, and infection in pregnancy causes congenital Zika syndrome, a devastating pattern of fetal brain injury including microcephaly. Most infection in children and adults is silent or a mild self-limiting illness, and the serious burden falls on the developing fetus and, more rarely, on adults who develop Guillain-Barré syndrome. Incidence has fallen since the epidemic peak, but low-level transmission continues in many countries, and there is still no licensed vaccine or specific treatment.

Discovery and historical significance

Zika virus was first isolated in 1947 from a sentinel rhesus monkey placed in the Zika Forest of Uganda, and shortly afterwards from Aedes mosquitoes at the same site. For decades it was known only as a cause of sporadic mild disease in Africa and Asia. The first sizeable outbreak occurred on Yap Island in 2007, followed by a large epidemic in French Polynesia in 2013 to 2014 during which the link with Guillain-Barré syndrome was first noticed. The virus then reached Brazil and spread explosively through the Americas from 2015, and the association with a surge in infant microcephaly led the World Health Organization to declare a Public Health Emergency of International Concern in February 2016.

Classification, structure, and genome

Classification

Zika virus belongs to the genus Orthoflavivirus (family Flaviviridae), current binomial Orthoflavivirus zikaense, within the Spondweni serocomplex. Two lineages are recognised, African and Asian, and the Pacific and American epidemic strains descend from the Asian lineage. It exists as a single serotype and, like all flaviviruses, its antibody cross-reacts strongly with related viruses, above all dengue.

Virion structure

The virion is a small enveloped particle about 50 nm in diameter, with envelope (E) and membrane (M) proteins on the surface. E mediates receptor binding and fusion and is the main neutralising target, arranged as 90 flat dimers in the herringbone lattice of the mature particle; immature particles are spiky and carry the uncleaved precursor membrane (prM) protein.

Genome organisation

The genome is a positive-sense single-stranded RNA of about 11 kb with a single open reading frame flanked by untranslated regions. It is translated as one polyprotein and cleaved into three structural proteins (capsid C, prM/M, envelope E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5), NS3 providing the protease and helicase, NS5 the polymerase and methyltransferase, and NS1 the secreted diagnostic antigen.

Replication cycle

Zika virus follows the canonical flavivirus cycle. The E protein binds attachment factors, including phosphatidylserine receptors of the TAM family that are abundant on the placental and neural cells relevant to its pathogenesis, and the particle enters by clathrin-mediated endocytosis. Endosomal acidification triggers E to rearrange into a fusogenic trimer that fuses the membranes and releases the genome. Translation and replication occur on endoplasmic-reticulum-derived vesicles with NS5 as the polymerase, immature particles bud into the endoplasmic reticulum, and maturation follows when furin cleaves prM to M in the trans-Golgi network.

Pathogenesis

Zika virus infects a wide range of cell types, but its defining feature is a tropism for fetal neural progenitor cells. In these cells it impairs proliferation and triggers cell death, interrupting the orderly growth of the cerebral cortex and producing the microcephaly and other brain malformations of congenital Zika syndrome; the placenta and fetal tissues sustain infection that seeds the fetal brain. The virus also persists in immune-privileged sites, notably the testis, for weeks to months, which underlies prolonged sexual transmissibility. In adults, the post-infectious Guillain-Barré syndrome is thought to be immune-mediated. As with other flaviviruses, the nonstructural proteins antagonise interferon responses, and pre-existing dengue antibody has been studied as a possible modifier of infection through antibody-dependent enhancement, though its clinical importance for Zika remains uncertain.

Epidemiology

Zika virus is transmitted mainly by Aedes mosquitoes, chiefly Aedes aegypti, with a sylvatic Aedes-and-monkey cycle in Africa. Its distinctive epidemiology is the additional non-vector routes: sexual transmission, documented from men and women and prolonged by testicular persistence, transmission in pregnancy from mother to fetus, and transmission by blood transfusion. Around 80% of infections are asymptomatic, so spread is largely silent and outbreaks can be extensive before they are recognised. Since the 2015 to 2016 epidemic, incidence has declined, but autochthonous mosquito-borne transmission has now been recorded in more than ninety countries across Africa, Asia and the Americas, and sporadic cases and small outbreaks continue.

Natural history

After an incubation of about 3 to 12 days, roughly four in five infections cause no symptoms at all. When illness does occur it is usually mild and lasts up to a week, and hospitalisation and death are rare. The serious outcomes are not features of the acute illness but its sequelae: congenital malformation when infection occurs in pregnancy, greatest after first-trimester infection, and post-infectious Guillain-Barré syndrome appearing days to weeks after an otherwise mild illness.

Clinical presentations and complications

Acute Zika is a mild illness of low-grade fever, a maculopapular rash, arthralgia and a characteristic non-purulent conjunctivitis, sometimes with headache and myalgia; it is clinically indistinguishable from mild dengue or chikungunya.

Congenital Zika syndrome is the defining complication. Infection in pregnancy, particularly in the first trimester, can cause microcephaly, intracranial calcification, ventriculomegaly, ocular lesions such as macular scarring, congenital contractures and sensorineural hearing loss, and a spectrum of later neurodevelopmental problems; infection can also cause miscarriage and stillbirth. Guillain-Barré syndrome, an ascending flaccid paralysis, is the main adult neurological complication and was the first severe outcome linked to the virus during the French Polynesian outbreak.

Diagnosis

Acute infection is confirmed by reverse-transcriptase PCR, and testing urine as well as blood is useful because viral RNA persists longer in urine than in serum. Beyond the first days, diagnosis relies on serology, which is difficult: Zika IgM cross-reacts strongly with dengue and other flaviviruses, so a positive result must be confirmed by plaque-reduction neutralisation, and interpretation is harder still in people with prior flavivirus exposure or vaccination. In pregnancy, maternal testing is combined with fetal ultrasound surveillance, and viral RNA can be sought in amniotic fluid and in neonatal samples.

Management

There is no antiviral, and treatment of the acute illness is supportive. The substance of management is preventive and anticipatory: counselling people who are pregnant or planning pregnancy, fetal ultrasound monitoring after maternal infection, and paediatric assessment and support of infants with congenital Zika syndrome. Guillain-Barré syndrome is managed as for other causes, with supportive and immune-modulating care.

Prevention and public health

Prevention combines mosquito-bite avoidance with measures unique to Zika’s transmission routes. Personal protection with repellents and clothing reduces bites, and because the virus is sexually transmitted and persists in semen, returning travellers are advised to use condoms or abstain for a defined period, with pregnant women advised to avoid travel to areas of active transmission and their partners to take precautions.

Vector control

Control of Aedes aegypti through source reduction, larviciding and community mobilisation is the mainstay of interrupting mosquito-borne spread, the same approach used for dengue and urban yellow fever.

Vaccination

There is no licensed vaccine, although several candidates across different platforms have advanced into clinical trials. Vaccine development is complicated by the need to protect pregnant women and by the theoretical concern that flavivirus antibody could enhance dengue infection.

Surveillance and notification

Because most infection is silent and the key harm is congenital, surveillance links arboviral case detection with monitoring of microcephaly and other congenital anomalies, supported by reference-laboratory confirmation.

South African context

Zika virus has not been shown to circulate autochthonously in South Africa, and the small number of recognised cases have been in travellers returning from affected regions. Competent Aedes aegypti vectors are present in warmer, low-lying parts of the country, so the theoretical potential for local transmission exists, but no sustained local spread has been documented. The practical concern is therefore in returning travellers, particularly pregnant women and their partners, for whom bite-avoidance, counselling on sexual transmission and, where indicated, fetal monitoring apply. Diagnostic testing is performed at the Arbovirus Reference Laboratory of the National Institute for Communicable Diseases, where the strong cross-reactivity with dengue makes confirmatory neutralisation and screening for other co-circulating arboviruses important, and suspected cases are reported through arboviral surveillance.

References and recommended reading

• Pierson TC, Lazear HM, Diamond MS. Flaviviruses: Dengue, Zika, West Nile, Yellow Fever and Other Flaviviruses. In: Fields Virology, 7th edition, Chapter 9. Philadelphia: Wolters Kluwer; 2023. The principal source for Zika pathogenesis, congenital disease and epidemiology.
• Lindenbach BD, Randall G, Bartenschlager R, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition, Chapter 7. Philadelphia: Wolters Kluwer; 2023. The source for virion structure, genome organisation and the replication cycle.
• Petersen LR, Barrett ADT. Arthropod-Borne Flaviviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition, Chapter 53. Washington: ASM Press; 2016. The foundational account of Zika discovery, transmission and clinical disease.
• World Health Organization. Zika virus. WHO fact sheet; 2025. The source for current global epidemiology, congenital Zika syndrome and vaccine status.
• Centers for Disease Control and Prevention. Zika Virus: Transmission and Pregnancy. CDC; 2025. The source for sexual and vertical transmission and prevention advice.