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This review summarizes the history and epidemiology of ZIKV.
This review outlines the transmission of ZIKV.
This review highlights the clinical presentation of ZIKV.
Zika virus (ZIKV), a mosquito-borne positive-stranded RNA virus of the family Flaviviridae (genus Flavivirus), is now causing an unprecedented large-scale outbreak in the Americas. Historically, ZIKV spread eastward from equatorial Africa and Asia to the Pacific Islands during the late 2000s to early 2010s, invaded the Caribbean and Central and South America in 2015, and reached North America in 2016. Although ZIKV infection generally causes no symptoms or only a mild self-limiting illness, it has recently been linked to a rising number of severe neurological diseases, including microcephaly and Guillain-Barré syndrome. Because of the continuous geographic expansion of both the virus and its mosquito vectors, ZIKV poses a serious threat to public health around the globe. However, there are no vaccines or antiviral therapies available against this pathogen. This review summarizes a fast-growing body of literature on the history, epidemiology, transmission, and clinical presentation of ZIKV and highlights the urgent need for the development of efficient control strategies for this emerging pathogen.
), which are transmitted by the bite of mosquitoes (27 species), ticks (12 species), or no known arthropod vector (14 species). Within the Flavivirus genus, ZIKV is a mosquito-borne virus that is phylogenetically closely related to other medically important mosquito-borne flaviviruses of global public health significance (Fig. 1), such as Japanese encephalitis (JEV), West Nile (WNV), dengue (DENV), and yellow fever (YFV) viruses (
): (1) encephalitic flaviviruses (represented by JEV and WNV), which cause invasive neurological diseases, with birds serving as their natural vertebrate hosts and Culex species mosquitoes as their principal vectors (
); and (2) non-encephalitic or viscerotropic flaviviruses (exemplified by DENV and YFV), which cause lethal hemorrhagic fever, with non-human primates acting as their vertebrate hosts and Aedes species mosquitoes as their primary vectors (
Discovered in Uganda in 1947, ZIKV was confined for the first 60 years to an equatorial zone across Africa and Asia. Outside this zone, however, it first emerged in Yap Island in 2007, spread eastward to French Polynesia and other Pacific Islands in 2013–2014, reached Latin America in 2015, and disseminated further to North America in 2016. Now, ZIKV is circulating in the Americas, Southeast Asia, and the Pacific Islands.
2.1 Virus discovery and seroprevalence in Africa and Asia prior to the year 2000
ZIKV was first isolated in 1947 from the serum of a sentinel rhesus macaque monkey that was placed in the Zika forest on the Entebbe peninsula, Uganda, during the course of surveillance for YFV (
). Despite the need for caution because of antibody cross-reactivity with other flaviviruses, a large number of serological studies in the half century since the discovery of ZIKV have revealed a broad but confined geographic distribution of human infection with the virus, across a relatively narrow equatorial belt running from Africa to Asia: Senegal (
2.2 The Yap outbreak and sporadic cases in Southeast Asia during the late 2000s to mid-2010s
Human illness caused by ZIKV infection was first reported in 1954 during an outbreak of jaundice in Nigeria, when infection was confirmed in three patients by isolation of the virus or a rise in serum antibody titer, with a correlation observed between the development of ZIKV neutralizing antibodies and jaundice (
). In 2007, however, ZIKV caused the first large outbreak outside of Africa and Asia on Yap Island, a part of the Federated States of Micronesia (Fig. 2) in the northwestern Pacific Ocean, with a relatively mild disease characterized by fever, rash, arthralgia, and conjunctivitis (
). During this outbreak, ~73% of the 6892 Yap residents aged ≥3 years were estimated to be infected with ZIKV, and ~18% of the infected people had a clinical illness that was probably attributable to ZIKV infection (
2.3 The French Polynesia outbreak and spread in the Pacific Islands in the early 2010s
In 2013–2014, a major epidemic of ZIKV occurred in French Polynesia (Fig. 2), a French overseas territory located in the middle of the southern Pacific Ocean, with its ~270,000 people living on 67 islands distributed among five archipelagoes (
). Although a vast majority of the clinical cases seen in this outbreak were similar to those observed in the 2007 Yap outbreak, a small fraction of severe cases were associated with neurological complications, such as Guillain-Barré syndrome, in the context of co-circulating DENV and chikungunya (
). In agreement with this finding, retrospective studies in French Polynesia indicated an increased number of instances of microcephaly and other fetal abnormalities after the 2013–2014 ZIKV outbreak (
). Since its emergence in Brazil, ZIKV has spread at an alarming rate throughout much of Central and South America and the Caribbean, and the possibility that microcephaly is linked to ZIKV has increased, prompting the World Health Organization to declare a “public health emergency of international concern” from February to November 2016 (
): Anguilla; Antigua and Barbuda; Argentina; Aruba; the Bahamas; Barbados; Belize; Bolivia; Bonaire, Sint Eustatius and Saba; Brazil; the British Virgin Islands; Cayman Islands; Colombia; Costa Rica; Cuba; Curaçao; Dominica; the Dominican Republic; Ecuador; El Salvador; French Guiana; Grenada; Guadeloupe; Guatemala; Guyana; Haiti; Honduras; Jamaica; Martinique; Mexico; Montserrat; Nicaragua; Panama; Paraguay; Peru; Puerto Rico; Saint Barthélemy; Saint Kitts and Nevis; Saint Lucia; Saint Martin; Saint Vincent and the Grenadines; Sint Maarten; Suriname; Trinidad and Tobago; Turks and Caicos Islands; the United States of America (US); the US Virgin Islands; and Venezuela (Fig. 2). Sexually transmitted cases have also been reported in Argentina, Canada, Chile, Peru, and the US (
). In November 2016, a decreasing trend in ZIKV cases had been noted in all the ZIKV-affected countries and territories in the Americas, except for Mexico, Panama, and the islands of Turks and Caicos (
). In the US states and federal districts, there were 4444 confirmed ZIKV cases reported to ArboNET as of November 23, 2016; of these, 36 were sexually transmitted cases throughout the country, and 182 were locally acquired mosquito-borne cases in Florida, where autochthonous transmission was first reported in July 2016 and is currently ongoing in the area of Miami Beach and in the county of Miami-Dade (
As illustrated in Fig. 2, ZIKV is a potential pandemic threat, currently circulating not only in the Americas but also in the Pacific Islands (American Samoa, Federated States of Micronesia, Fiji, Marshall Islands, New Caledonia, Palau, Papua New Guinea, Samoa, and Tonga), Southeast Asia (Singapore, Thailand, the Philippines, and Vietnam), and the islands of Cape Verde off the coast of West Africa (
). Using species distribution modeling techniques, a recent study has predicted that a large portion of the tropical and sub-tropical regions of the globe has suitable environmental conditions but has not yet reported symptomatic cases of ZIKV infection (Fig. 3), with over two billion people living in these areas (
). Thus, the presence of a much larger susceptible population in suitable environments for ZIKV, combined with its travel-mediated rapid dissemination, has raised concerns about the high risk of introducing and establishing new autochthonous transmission in these areas (
). The situation is particularly challenging in the US, because ZIKV is likely to spread further, from Florida to other southern states (Fig. 3, inset), given the estimated range of the two major competent mosquito vectors, A. aegypti and A. albopictus (
). For the same reason, it is very likely that ZIKV will become endemic in the Americas.
3. Genetic diversity
During the seven decades since its accidental discovery in 1947, >500 ZIKV isolates have been obtained sporadically in Africa, Asia, the Pacific Islands, and the Americas, but only a very limited number of these strains have been fully sequenced (
). As shown in Fig. 4, a phylogenetic analysis using the nucleotide sequence of all 29 complete or near-complete ZIKV genomes retrievable from GenBank (as of May 2016) revealed that the geographically and temporally distinct ZIKV strains can be grouped into two major genetic lineages, African and Asian, with all eighteen 2015–2016 American epidemic strains derived from a common ancestor of the Asian lineage (
). Moreover, the most recent data from phylogenetic and molecular clock analyses suggest that the 2015–2016 American epidemic began with a single introduction of ZIKV into the Americas during May–December 2013, along with the increase in air traffic from ZIKV-endemic areas to Brazil and the emergence of ZIKV in the Pacific Islands (
). Despite its considerable degree of genetic variation, little is known about the impact of viral genetic variation on the pathogenicity of ZIKV of the African and Asian lineages, as well as among different strains within the Asian lineage (
). Thus, more research is needed to extend our understanding of the evolution and diversity of ZIKV and to explore the biological effects of viral genetic variation on the outcome of ZIKV infection.
ZIKV is transmitted to humans primarily through the bite of infected mosquitoes, but it can also be passed from mother to child during pregnancy or spread through sexual contact, breastfeeding, or blood transfusion. The multiple modes of ZIKV transmission make it difficult to develop control strategies against the pathogen.
4.1 Vector-borne transmission
ZIKV is an arthropod-borne virus (arbovirus) that is transmitted by mosquito vectors, with two distinct transmission cycles (
): (i) a sylvatic cycle, involved in the maintenance of ZIKV between non-human primates and arboreal mosquitoes in forests; and (ii) an urban cycle, involved in the transmission of ZIKV between humans and urban mosquitoes in towns (Fig. 5). Occasionally, the virus is presumably transmitted by arboreal mosquitoes from non-human primates to humans when they are in close proximity. ZIKV has been isolated in Africa and Asia from a number of different mosquito species in the genus Aedes (e.g., A. aegypti, A. africanus, A. albopictus, A. apicoargenteus, A. furcifer, A. luteocephalus, A. opok, and A. vittatus), which can potentially act as vectors for viral transmission in a given environment of those endemic areas (
In an urban cycle, the transmission of ZIKV is believed to be mediated predominantly by two Aedes species mosquitoes: A. aegypti, recognized by a bright lyre-shaped dorsal pattern with white bands on its legs, and A. albopictus, characterized by a single longitudinal dorsal stripe with white bands on its legs (
). As a secondary vector for ZIKV, A. albopictus has been suggested to be involved in the urban transmission in Gabon, where five human sera and two A. albopictus pools collected in an urban setting in 2007 were positive for ZIKV (
). Because of its high invasive ability and wide geographic distribution in tropical and temperate regions, there is a high potential for A. albopictus to become a major vector for the urban transmission of ZIKV across the globe.
Both A. aegypti and A. albopictus are usually active during daylight hours (
). In the US, both A. aegypti and A. albopictus are present in practically the entire southern and southeastern half of the country (Fig. 3, inset map), according to a recent estimate by the Centers for Disease Control and Prevention (
). A recent study has shown that although they are susceptible to ZIKV infection, American populations of both A. aegypti and A. albopictus collected from Florida have unexpectedly low levels of vector competence (the mosquito's ability to biologically transmit ZIKV) (
). However, A. aegypti (and to a lesser extent A. albopictus) is thought to have a high level of vectorial capacity (a measurement of the efficiency of ZIKV transmission) because it primarily bites humans, infects several persons during a single blood meal, and lives in close association with humans (
). These mosquito species may contribute to the transmission of ZIKV in particular environments, but the mere isolation of the virus from mosquitoes or its detection in the mosquitoes does not necessarily identify it as an actual vector. Further field and experimental studies are needed to better define vector competence for ZIKV and to determine whether there are any other mosquito vectors or animal hosts.
4.2 Non-vector-borne transmission
Direct human-to-human transmission of ZIKV has been documented to occur perinatally, sexually, and through breastfeeding or blood transfusion: (i) ZIKV can be passed from an infected mother to her fetus during pregnancy, as evidenced not only by the detection of viral RNA in the amniotic fluid, urine, or serum of mothers whose fetuses had brain abnormalities (
). (ii) ZIKV can be sexually transmitted from an infected person to his or her partners, as shown by the detection of the virus in patient's semen, often in high titer, and transmission of the virus between both sexes, with the male-to-female transmission occurring more frequently than female-to-male or male-to-male transmission (
). (v) Direct transmission, although uncommon, can take place through the skin or mucous membranes, as exemplified by the index patient, who had a high viral load of 2 × 108 genome copies per ml in serum (
). Although these non-vector-borne transmissions of ZIKV are believed to be uncommon, further studies are necessary to identify the risk factors involved in these routes of viral transmission.
ZIKV, a 50-nm enveloped particle, contains an inner nucleocapsid composed of a linear plus-strand genomic RNA and multiple copies of the viral capsid (C) protein and the outer host cell-derived lipid bilayer bearing 180 copies each of two proteins: the viral membrane (M, a cleavage product of prM) protein and the envelope (E) protein (
) (Fig. 6A ). The ORF encodes a large polyprotein of 3423 amino acids (aa), which is predicted to be cleaved by viral and cellular proteases into at least 10 individual proteins, designated in an N- to C-terminal direction (
There are very few direct experimental data available concerning the replication cycle of ZIKV, but the current understanding of the molecular biology of other flaviviruses provides a clear path forward for ZIKV research (
). When the virions are delivered to endosomes, the E glycoprotein undergoes a series of low pH-induced structural changes, enabling the fusion of the viral membrane with the endosomal membrane and the release of the viral genome into the cytoplasm (
). Viral RNA replication takes place in close association with virus-induced intracellular membrane structures known as replication complexes, which contain the viral RNA and proteins, as well as presumably a set of the host cell factors required for viral RNA synthesis (
). For future studies, it is important to understand the similarities and differences in molecular biology between ZIKV and other relatively well-characterized flaviviruses (e.g., JEV, WNV, DENV, and YFV), with respect to viral replication and pathogenesis.
6. Clinical presentation
ZIKV can produce a wide variety of clinical symptoms in humans. A growing body of evidence suggests that in some severe cases, ZIKV causes neurological diseases, such as Guillain-Barré syndrome in ZIKV-infected adults and microcephaly in infants born to ZIKV-infected women.
6.1 Common signs and symptoms
ZIKV infections are symptomatic in only ~20–25% of the infected individuals who develop a mild and self-limited illness, with an incubation period of 4–10 days (
). In symptomatic cases, the common symptoms are nonspecific and resemble those of a flu-like syndrome, including transient low-grade fever, itchy maculopapular rash, arthritis or arthralgia, and nonpurulent conjunctivitis; at a lesser frequency, retro-orbital pain, headache, myalgia, edema, and vomiting are seen (
). More definitively, a recent case-control study revealed that anti-ZIKV IgM or IgG was detected in 41 (98%) of 42 patients with Guillain-Barré syndrome, and all had neutralizing antibodies against ZIKV, as compared to 54 (55%) of 98 controls: age-, sex- and residence-matched patients with a non-febrile illness (
). Thus far, ZIKV-induced Guillain-Barré syndrome has been transient, and most patients have recovered fully. Currently, the mechanism by which ZIKV infection leads to Guillain-Barré syndrome is unknown but is under active investigation.
Microcephaly is a neurological condition in which the brain of a baby does not develop properly, causing the head to be smaller than normal (