Zika Virus

Zika virus (ZIKV) belongs to the Flavivirus genus; like other flaviviruses, Zika virus is an icosahedral, enveloped, single-stranded RNA virus. ^{[1, 2]}  The lipid envelope is covered with dense projections that consist of a membrane and envelope glycoproteins. ^[2]  

In most cases, Zika virus infection causes a mild, self-limited illness. The incubation period is around 3-14 days. ^[1]  The spectrum of Zika virus disease overlaps with other arboviral infections, but rash (maculopapular and likely immune-mediated) typically predominates. ^[1]  Unlike other arboviral infections, Zika virus has potential for sexual transmission ^[1]  and has been associated with congenital brain abnormalities in pregnant women infected during the first trimester. 

Zika virus was first described in a captive sentinel febrile rhesus monkey in the Zika forest of Entebbe, Uganda in 1947. In 1948, the virus was recovered from the mosquito Aedes africanus in the Zika forest. The first human case was reported shortly thereafter in 1952. ^{[1, 2]}  Zika virus is widely distributed outside Africa. Outbreaks have been described in Micronesia and French Polynesia. ^{[3, 4]}  A large outbreak of Zika was declared in the Americas in 2015-2016 that later spread mostly via travel to US states. In February 2016, the World Health Organization (WHO) declared the spread of Zika virus a public health emergency. ^[5]  Since 2017, Zika cases have declined, and as of January 2021, no countries in the world report active Zika virus infection outbreaks. ^[6]

Zika virus infection is among the nationally notifiable diseases in the United States since 2016. Healthcare professionals should inform state and local health departments of suspected cases of ZIKV infection to facilitate diagnosis and to reduce the risk of local transmission. 

For the latest information concerning Zika virus, see also Medscape’s Zika Virus Resource Center.

The genome of the Zika virus has a length of 10.7 kb, divided into structural and non-structural segments. There are 3 structural proteins (core [C], pre-membrane [prM], and envelope [E]) and 7 non-structural (NS) proteins. ^[1]  The prM and E proteins facilitate viral attachment to the host cell membrane AXL receptor, a transmembrane receptor tyrosine kinase protein. This is followed by endocytic uptake and then uncoating of the nucleocapsid and release of viral RNA into the cytoplasm. The NS proteins form a replication complex that synthesizes positive-sense RNA from negative-sense RNA. A viral polyprotein is produced and modified by the endoplasmic reticulum. Immature virions collect both in the endoplasmic reticulum and in secretory vesicles before being released. The C protein along with other NS proteins cause cell cycle arrest, apoptosis and death. ^{[1, 2]}   

Sirohi et al described the structure of mature ZIKV based on cryoelectron microscopy. The virus resembles other known flavivirus structures with the exception of approximately 10 amino acids surrounding the Asn154 glycosylation site in each of the 180 envelope glycoproteins comprising the icosahedral shell, the carbohydrate moiety that may be the site where the virus attaches to the host cells. ^[7]

Zika virus has 2 Zika virus lineages (Asian and African) and 3 genotypes (West African, East African, and Asian) based on phylogenetic analysis. ^[1]  The Asian lineage spread from Asia to the Pactific Islands and the Americas. It is poorly understood if these lineages have any impact on clinical outcomes. It is speculated that Zika virus Asian lineage is associated with serious outbreaks and congenital malformations and that African lineage is intrinsically more virulent and is associated with acute infection and adverse pregnancy outcomes. ^[8]

Zika virus is well-adapted to grow in various hosts, ranging from arthropods to vertebrates. Zika virus has tropism for various tissues in the human body such as skin, blood, placenta cells, testes, retinal cells, neural stem cells and neuroprogenitor cells. Zika virus also infects monocytes, facilitating passage across blood-brain and placental barriers. Host cells invaded by Zika virus undergo cellular appoptosis, necrosis, and death. Thus, Zika virus affecting neuronal progenitor cells affects neuronal growth, causing fetal brain abnormalities and placental insufficiency resulting in fetal loss. ^[9]  

The first defense against Zika virus is produced by the innate immune system. ^[10] Activation of type I interferon (IFN) and IFN-stimulated genes (ISG) inhibits Zika virus replication. Zika virus is able to evade the immune response with the help of NS proteins inhibiting the signaling pathway responsible for activation of IFN and ISG. ^[10] Studies have demonstrated inhibition of stress granule formation and modulation of nonsense-mediated mRNA decay machinery by Zika virus, enhancing its viral replication. Further studies are needed to completely understand the mechanisms behind Zika virus's evasion of the immune response. ^[11]  

Research has demonstrated interaction between ZIKV and dengue virus immune response impacting immunogenicity and disease complications. Studies have demonstrated a lower seroprevalence of dengue virus in Zika virus infected mothers of children with congenital Zika syndrome and mothers with vertical transmission of Zika virus to the fetus. This is suggestive of potential cross-protection against Zika virus in those with previous history of dengue virus infection. The CD4+ and CD8+ T cell response from dengue virus infection has been demonstrated to suppress Zika virus replication, imparting protection against Zika virus infection. On the contrary, previous Zika virus infection has been shown to increase the risk for severe disease in those with dengue virus infection. ^[8]   

The global prevalence of Zika virus infection has not been widely reported owing to asymptomatic clinical course, clinical resemblance to other infection with other flaviviruses (dengue, chikungunya), and difficulty in confirming diagnosis.

Based on outbreak reports, entomologic surveys, and seroprevalence surveys, Zika virus infection had been reported in various hosts, including humans, primates, and mosquitoes, in a total of 87 countries and territories across Africa, the Americas, Southeast Asia, and the Western Pacific, as of July 2019. ^[12]

The prevalence of Zika virus infection in Uganda was 6.1% in 1952 among a population of 99 residents. ^[13] The prevalence of Zika virus infection was 7.1% in Java, Indonesia, from 1977-1978 among patients who were hospitalized for fever. ^[14]  A seroprevalence of around 20-22% was estimated based on study survey in Senegal, Mali and Gambia from 2007-2012. ^[1]

Since Zika virus was first isolated in 1947, the disease has spread outside Africa, mainly into Southeast Asia and the Americas. Until 2007, sporadic cases of Zika virus illness in humans were reported. In 2007, Yap Island in Micronesia reported an outbreak of Zika virus infection transmitted via Aedes hensilli that sickened approximately 73% of the population. ^[4] Since 2013-2015, epidemics of Zika virus infection have occurred in French Polynesia, New Caledonia, the Cook Islands, the Easter Islands, and other Pacific Islands. ^[15]  The outbreak in French Polynesia highlighted Guillian-Barre syndrome as a potential neurologic complication associated with Zika.

In May 2015, Brazil reported the first outbreak of Zika virus infection in the Americas, accounting for around 205,578 cases, in 2016. The Asian lineage associated with the outbreak had potentially circulated in Brazil since 2013. Aedes aegypti (major) and Aedes albopictus (minor) were recognized as vectors for the transmission of Zika virus. The infection spread rapidly to several other countries and became a pandemic. During the outbreak in Brazil, a notable 22% rise in hospitalizations occured between 2014 to 2015 due to Zika-associated Guillain-Barré syndrome (GBS); confirmed or suspected cases of congenital Zika syndrome were reported in more than 5,000 newborns. ^{[16, 17]}  Brazil reported a total of 6 deaths in 2015-2016. The incidence of new cases eventually decreased due to herd immunity. 

Before 2015, only 14 travel-associated cases of Zika virus disease were reported in the United States. In 2016, around 5,168 laboratory-confirmed non-congenital Zika virus infections were reported in the United States. Most (95%) cases were imported as a result of travel to areas with ongoing outbreaks, 4% were potentially acquired via local vector-borne transmission in Florida and Texas, and 1% of the cases were acquired through other routes (sexual transmission, laboratory-acquired and unknown source). Guillain-Barré syndrome was reported in 0.3% of cases, of which 3% required hospitalization. Zika-associated birth defects occured in 10% of babies born to women in the United States. ^{[18, 19]}

United States territories such as Puerto Rico and the US Virgin Islands have reported around 37,188 symptomatic Zika virus disease cases, the majority of which were related to autochthonous transmission of the virus. Around 5% of babies born to women in US territories had Zika-associated birth defects. ^[18]

Outside of Americas and US states and territories, Cape Verde reported the first African Zika epidemic in 2015-2016. Ethiopia reported evidence of Zika virus infection in 2018. Multiple countries in Southeast Asia such as India, Indonesia, Mynamar, and Thailand have reported Zika virus cases and associated complications. ^[12]  

Zika virus infections have been reported in Europe since 2013. The European CDC reported 71 cases of Zika virus infection in 2019, the majority  (92%) of which were travel associated with few locally transmitted as a result of sexual contact or vertical transmission. The first 3 cases of vector-borne local transmission of ZIKV infection via Ae albopictus were reported in France in October 2019. ^[20]

Laboratory-confirmed symptomatic Zika virus disease cases reported to ArboNET by states and territories - United States, 2017. Courtesy of the Centers for Disease Control and Prevention (CDC).

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World map of areas with color-coded risk for Zika based on current or previously reported Zika cases, as of November 4, 2019. Courtesy of the Centers for Disease Control and Prevention (CDC).

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Most cases of Zika virus infection are mild and self-limited. Owing to the mild nature of the disease, more than 80% of Zika virus infection cases likely go unnoticed. ^[1]  

Serious neurologic complications have been reported in rare cases, including Guillain-Barré syndrome. ^{[1, 21]}

In addition, adverse pregnancy outcomes and congenital Zika syndrome due to vertical transmission of Zika virus are of greatest concern with poor long-term prognosis. ^{[14, 22]}  

Zika virus infection has short-term adverse effects on fertility.

For further detail, see History.

Patients should be educated concerning travel risks associated with Zika virus and prevention of mosquito bites and mosquito-control measures. Travelers should refer to CDC site before arranging travel plans for up-to-date information on Zika virus transmission internationally and in US states and territories.

The CDC provides information for women who are pregnant or trying to get pregnant on implications of Zika virus infection during pregnancy and helpful travel, testing, and management information related to the topic. ^[23]

The World Health Organization (WHO) and CDC recommend that mothers with Zika virus infection still breastfeed their infants, including those born with microcephaly. Zika virus has been isolated from breast milk but the risk for transmission via breast milk has not been documented. ^[24]

For more details, see Prevention.

Zika virus can be transmitted by vector-borne and non-vector-borne routes. 

Vector-borne Transmission

Like many other flaviviruses, Zika virus is transmitted by an arthropod: the Aedes mosquito, including Aedes aegypti, Aedes africanus, Aedes luteocephalus, Aedes albopictus, Aedes vittatus, Aedes furcifer, Aedes hensilli, and Aedes apicoargenteus. ^{[1, 2, 4, 25]}  Zika virus has also been isolated from domestic mosquito Culex quinquefasciatus. Zika virus circulates among different human and animal species with the mosquito as the vector of transmssion. The sylvatic cycle transmits Zika virus between non-human primates, and the urban life cycle infects humans. Ae. aegypti, a major vector for human transmission, and Ae. albopictus, a minor vector with few reported outbreaks, are typically found in tropical and subtropical regions and have also been discovered in other non-tropical parts of the world. The CDC has released a map of potential ZIKV spread in the United States based on the estimated range of Aedes aegypti and Aedes albopictus mosquitoes. 

In United States, transmission is active in months of June to October while the mosquito vectors feeds on humans during daytime. Zika virus is transmitted from the salivary gland of the biting mosquito into the host's blood circulation and subsequently infects the skin cells and other organs. ^[26]

Non-vector-borne Transmission

Zika outbreaks unearthed various non-vector-borne transmission routes of Zika virus. 

Vertical transmission of Zika virus from mother to fetus is estimated to occur in 20-30% of infected pregnant women during all trimesters. Infection during the first trimester is considered most serious and is associated with congenital Zika syndrome. Zika virus has also been isolated in breastmilk; however, there is no clear evidence of transmission to babies during breastfeeding. Breastfeeding is encouraged in Zika virus-infected or possibly infected mothers as the benefits of breastfeeding outweigh the risks. ^{[1, 27]}  

Zika virus has been idenitified in the semen of 50-60% of men in the first month of infection, lasting up to 281 days in one case. Cases of sexual transmission of Zika virus from male-to-female partners has been reported in the United States and French Polynesia. Transmission from female-to-male and male-to-male partners has also been reported. The highest risk for sexual transmission from an infected partner is estimated to occur up to 32-44 days from the onset of symptoms. ^{[1, 2, 28]}

Zika virus can be detected in the serum for a short time during acute illness. The estimated prevelance of Zkia virus RNA in blood donors is around 1%. Blood tranfusion-related transmission of Zika virus remains a concern. Zika virus has been isolated in urine, saliva, and solid organs during transplantation; however, there is no clear evidence of transmission from these routes. ^{[1, 2, 29]}