Journal of Neuroimmunology 308 (2017) 50–64

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Journal of Neuroimmunology

journal homepage: www.elsevier.com/locate/jneuroim

Review article

Zika virus: History, epidemiology, transmission, and clinical presentation

Byung-Hak Song, Sang-Im Yun, Michael Woolley, Young-Min Lee ⁎
Department of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA

a r t i c l e i n f o a b s t r a c t

Article history: Zika virus (ZIKV), a mosquito-borne positive-stranded RNA virus of the family Flaviviridae (genus Flavivirus), is
Received 22 December 2016 now causing an unprecedented large-scale outbreak in the Americas. Historically, ZIKV spread eastward from
Received in revised form 1 March 2017 equatorial Africa and Asia to the Pacific Islands during the late 2000s to early 2010s, invaded the Caribbean
Accepted 1 March 2017
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
Keywords:
Zika virus
neurological diseases, including microcephaly and Guillain-Barré syndrome. Because of the continuous geo-
Flavivirus graphic expansion of both the virus and its mosquito vectors, ZIKV poses a serious threat to public health around
Arbovirus the globe. However, there are no vaccines or antiviral therapies available against this pathogen. This review sum-
Mosquito-borne pathogen marizes a fast-growing body of literature on the history, epidemiology, transmission, and clinical presentation of
Zika outbreak ZIKV and highlights the urgent need for the development of efficient control strategies for this emerging
Zika pandemic pathogen.
Microcephaly © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
Guillain-Barré syndrome
(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Classification and nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

2. History and epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
2.1. Virus discovery and seroprevalence in Africa and Asia prior to the year 2000 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
2.2. The Yap outbreak and sporadic cases in Southeast Asia during the late 2000s to mid-2010s . . . . . . . . . . . . . . . . . . . . . . . . 52
2.3. The French Polynesia outbreak and spread in the Pacific Islands in the early 2010s . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
2.4. The Brazil outbreak and spread in the Americas in 2015–2016 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
2.5. Current status and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3. Genetic diversity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4. Transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
4.1. Vector-borne transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4.2. Non-vector-borne transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
5. Virology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
6. Clinical presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.1. Common signs and symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.2. Guillain-Barré syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.3. Microcephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
6.4. Other neurological complications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
7. Tissue and cell tropism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

⁎ Corresponding author at: Department of Animal, Dairy, and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, 9830 Old Main Hill, Logan, UT
84322, USA.
E-mail address: youngmin.lee@usu.edu (Y.-M. Lee).

http://dx.doi.org/10.1016/j.jneuroim.2017.03.001
0165-5728/© 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64 51

1. Classification and nomenclature
Zika virus (ZIKV) belongs to the genus Flavivirus in the family
Flaviviridae (Lindenbach et al., 2007). Currently, the genus comprises
53 virus species (Simmonds et al., 2012), which are transmitted by the
bite of mosquitoes (27 species), ticks (12 species), or no known arthro-
pod 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 signifi-
cance (Fig. 1), such as Japanese encephalitis (JEV), West Nile (WNV),
dengue (DENV), and yellow fever (YFV) viruses (Gubler et al., 2007).
These mosquito-borne flaviviruses can be divided into two major clas-
ses based on their clinical presentation in humans (Gaunt et al., 2001;
Kramer and Ebel, 2003): (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 (Brinton, 2013; Yun and Lee, 2014); 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 mos-
quitoes as their primary vectors (Monath and Vasconcelos, 2015;
Weaver and Barrett, 2004). Of note, DENV has fully adapted to humans
and no longer needs animal hosts for viral transmission (Clyde et al.,
2006; Mackenzie et al., 2004).
2. History and epidemiology
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 (Dick
et al., 1952). This isolate, named MR-766, is the African prototype
strain of ZIKV. Shortly thereafter, it was also recovered on multiple oc-
casions from A. africanus mosquitoes caught in the same area (Dick,
1952; Dick et al., 1952; Haddow et al., 1964; Weinbren and
Williams, 1958). Although there was no indication that ZIKV caused
disease in the residents of Uganda, the prevalence of antibodies
against the virus in their serum was approximately 10–20% (Dick,
1953; Dick et al., 1952). Despite the need for caution because of anti-
body cross-reactivity with other flaviviruses, a large number of sero-
logical studies in the half century since the discovery of ZIKV have
revealed a broad but confined geographic distribution of human infec-
tion with the virus, across a relatively narrow equatorial belt running
from Africa to Asia: Senegal (Monlun et al., 1993), Sierra Leone (Robin
and Mouchet, 1975), Nigeria (Adekolu-John and Fagbami, 1983;
Fagbami, 1977; Macnamara, 1954), Gabon (Jan et al., 1978; Saluzzo
et al., 1982), Central African Republic (Saluzzo et al., 1981), Egypt
(Smithburn et al., 1954b), Uganda (Smithburn, 1952), Tanzania

Fig. 1. A rooted phylogenetic tree based on the nucleotide sequence of complete or near-complete genomes of all 46 available flaviviruses (as of November 2016). Multiple sequence
alignments were produced by ClustalX (Thompson et al., 1997), and the rooted phylogenetic tree was generated by the neighbor-joining method (Saitou and Nei, 1987). The scale bar
represents the genetic distance in nucleotide substitutions per site. Bootstrap values (1000 replications) are shown at each node. The complete genome sequence of the bovine viral
diarrhea virus, a member of the genus Pestivirus in the family Flaviviridae, was used as an outgroup. The virus abbreviations assigned by the International Committee on Taxonomy of
Viruses are listed, and the strain names and their GenBank accession numbers are provided in parenthesis. The known or probable vector (mosquito or tick) is indicated on the right
side of the tree.
52 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64

(Smithburn, 1952), Kenya (Geser et al., 1970), Pakistan (Darwish
et al., 1983), India (Smithburn et al., 1954a), Thailand (Pond, 1963),
Malaysia (Pond, 1963; Smithburn, 1954), Vietnam (Pond, 1963),
Indonesia (Olson et al., 1983), and the Philippines (Hammon et al.,
1958). In 1966, the first non-African ZIKV strain, designated P6-740,
was isolated from a pool of A. aegypti mosquitoes collected in
Malaysia (Marchette et al., 1969).
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 con-
firmed in three patients by isolation of the virus or a rise in serum anti-
body titer, with a correlation observed between the development of
ZIKV neutralizing antibodies and jaundice (Macnamara, 1954). From
that time until the early 2000s, only about a dozen cases of benign
human ZIKV-associated illness were documented in countries in Africa
and Asia (Hayes, 2009), such as Uganda (Simpson, 1964), Nigeria
(Fagbami, 1979; Moore et al., 1975), and Indonesia (Olson et al.,
1981). 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
(Duffy et al., 2009; Lanciotti et al., 2008). 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 (Duffy et al., 2009). Se-
quence analysis suggested that ZIKV was introduced to Yap Island
from Southeast Asia (Duffy et al., 2009; Haddow et al., 2012; Lanciotti
et al., 2008). In the early to mid-2010s, a handful of sporadic cases of
ZIKV infection were also reported in Southeast Asian countries, such
as Thailand (Buathong et al., 2015; Tappe et al., 2014), Cambodia
(Heang et al., 2012), Malaysia (Tappe et al., 2015), Indonesia (Kwong
et al., 2013; Perkasa et al., 2016), and the Philippines (Alera et al., 2015).
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 Polyne-
sia (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 (Cao-Lormeau et al., 2014). Dur-
ing this outbreak, ~11% of the total population was estimated to have
sought medical treatment for suspected ZIKV infection (ECDC, 2014;
Mallet et al., 2015; Musso et al., 2014b). The magnitude of the outbreak
was presumably the result of a combination of the low level of pre-
existing immunity to ZIKV and the high density of competent mosquito
vectors in that area (Aubry et al., 2015). 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 (ECDC, 2014; Oehler
et al., 2014). Retrospectively, the incidence of Guillain-Barré syndrome
was estimated to be increased by ~20-fold in French Polynesia (Oehler
et al., 2014). Although the origin of the ZIKV in French Polynesia remains
unknown, it is genetically related to the strains isolated from Yap Island
in 2007 and from Cambodia in 2010 (Cao-Lormeau et al., 2014). During
or shortly after the French Polynesia outbreak, ZIKV spread further to
other neighboring islands in the South Pacific Ocean (Cao-Lormeau
and Musso, 2014; Musso et al., 2015a; Musso et al., 2014b), including
New Caledonia (Dupont-Rouzeyrol et al., 2015), the Cook Islands
(Roth et al., 2014), and Easter Island (Tognarelli et al., 2016). Also, it
was imported to other faraway countries such as Australia (Pyke et al.,
2014), Italy (Zammarchi et al., 2015a), Japan (Kutsuna et al., 2014),
and Norway (Waehre et al., 2014).

Fig. 2. Countries and territories that have reported autochthonous mosquito-borne transmission of ZIKV in the past 3 months. The term “widespread transmission” (red) indicates one of
the following three situations: (1) more than 10 locally transmitted ZIKV cases reported in a single area, (2) at least two separate areas reporting locally transmitted ZIKV cases, and
(3) ZIKV transmission ongoing in an area for more than 3 months. The term “sporadic transmission” (orange) indicates that no more than 10 locally transmitted ZIKV cases have been
reported in a single area in the past 3 months. The term “past transmission” (blue) indicates that local ZIKV transmission has been reported since 2007, but not in the past 3 months.
Source: European Centre for Disease Prevention and Control, current status of ZIKV transmission in the world as of November 23, 2016 (http://ecdc.europa.eu/en/healthtopics/zika_virus_
infection/zika-outbreak/pages/zika-countries-with-transmission.aspx).
 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64
2.4. The Brazil outbreak and spread in the Americas in 2015–2016
At the beginning of 2015, the first autochthonous transmission of
ZIKV was detected in the northeastern part of Brazil (Campos et al.,
2015; Zammarchi et al., 2015b; Zanluca et al., 2015), in association
with an outbreak of an acute exanthematous illness (Cardoso et al.,
2015). Toward the end of 2015, ZIKV activity expanded into at least 14
Brazilian states (WHO, 2015), with an estimated 440,000–1,300,000
suspected cases (Hennessey et al., 2016). To our surprise, it was noted
in Brazil that the number of newborn infants with microcephaly had in-
creased in the ZIKV-affected areas by September 2015 (Schuler-Faccini
et al., 2016), and N4000 cases of suspected microcephaly were reported
by February 2016, although these cases may have been misdiagnosed in
some cases or over-reported (Victora et al., 2016). In agreement with
this finding, retrospective studies in French Polynesia indicated an in-
creased number of instances of microcephaly and other fetal abnormal-
ities after the 2013–2014 ZIKV outbreak (Cauchemez et al., 2016;
Jouannic et al., 2016). In October 2015, Colombia reported the local
transmission of ZIKV infection outside Brazil (WHO, 2015), and by
March 2016, a total of 51,473 suspected ZIKV infections were recorded
in that country, with 2090 laboratory-confirmed cases (WHO, 2016a).
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 (WHO, 2016c, 2016d). ZIKV is still causing an unprecedented on-
going epidemic in Latin America and threatening North America and po-
tentially the rest of the world (Fauci and Morens, 2016; Lessler et al.,
2016).
As of November 17, 2016, 48 countries and territories in the
Americas had reported the autochthonous mosquito-borne transmis-
sion of ZIKV (PAHO/WHO, 2016a), with an accumulated number of
171,553 confirmed cases (PAHO/WHO, 2016b): 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 (PAHO/WHO, 2016a). 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 (PAHO/WHO, 2016a). To date, a total of 20
countries and territories in the Americas have documented 2311 con-
firmed cases of ZIKV-associated congenital syndrome (PAHO/WHO,
2016a, 2016b). 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 cur-
rently ongoing in the area of Miami Beach and in the county of Miami-
Dade (CDC, 2016b, 2016f). By November 17, 2016, a total of 33 newborn
infants and pregnancy losses with birth defects had been reported to the
US Zika Pregnancy Registry (CDC, 2016d).
2.5. Current status and future prospects
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
53
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 (CDC,
2016a; ECDC, 2016a; WHO, 2016b). In addition, since early 2015,
there have been an increasing number of travel-related imported ZIKV
cases in non-endemic countries: Australia (AGDH, 2016; Pyke et al.,
2016), Belgium (De Smet et al., 2016), Canada (GC, 2016), China (Yin
et al., 2016; Zhang et al., 2016b), France (Maria et al., 2016), the US
(Hawaii) (CDC, 2016b), Italy (Nicastri et al., 2016b), Portugal (Ze-Ze
et al., 2016), Spain (Diaz-Menendez et al., 2016), Switzerland
(Gyurech et al., 2016), and the Netherlands (Duijster et al., 2016).
Using species distribution modeling techniques, a recent study has pre-
dicted 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 peo-
ple living in these areas (Messina et al., 2016). Thus, the presence of a
much larger susceptible population in suitable environments for ZIKV,
combined with its travel-mediated rapid dissemination, has raised con-
cerns about the high risk of introducing and establishing new autoch-
thonous transmission in these areas (Bogoch et al., 2016; Fauci and
Morens, 2016; Gatherer and Kohl, 2016; Musso and Gubler, 2016).
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 (CDC, 2016e). 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,
N500 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 (Baronti et al., 2014; Barzon
et al., 2016a; Berthet et al., 2014; Cunha et al., 2016; Ellison et al.,
2016; Giovanetti et al., 2016; Kuno and Chang, 2007; Ladner et al.,
2016; Lanciotti et al., 2008; Lednicky et al., 2016; Liu et al., 2016; Zhu
et al., 2016). As shown in Fig. 4, a phylogenetic analysis using the nucle-
otide sequence of all 29 complete or near-complete ZIKV genomes re-
trievable 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 ances-
tor of the Asian lineage (Yun et al., 2016). This spatiotemporal relation-
ship is consistent with recent reports (Calvet et al., 2016; Enfissi et al.,
2016; Faria et al., 2016; Faye et al., 2014; Haddow et al., 2012;
Lanciotti et al., 2016; Mlakar et al., 2016; Wang et al., 2016). Moreover,
the most recent data from phylogenetic and molecular clock analyses
suggest that the 2015–2016 American epidemic began with a single in-
troduction 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 (Faria et al., 2016). De-
spite 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 (Wang et al., 2016). 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.
4. Transmission
ZIKV is transmitted to humans primarily through the bite of infected
mosquitoes, but it can also be passed from mother to child during preg-
nancy or spread through sexual contact, breastfeeding, or blood transfu-
sion. The multiple modes of ZIKV transmission make it difficult to
develop control strategies against the pathogen.
54 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64

Fig. 3. Global environmental suitability for ZIKV. Highlighted are the countries that are highly environmentally suitable, having a suitable area of more than 10,000 km2, but not yet
reporting symptomatic ZIKV cases (Source:Messina et al., 2016). An inset shows an estimated range for A. aegypti and A. albopictus in the US.
Source: Centers for Disease Control and Prevention (https://www.cdc.gov/zika/vector/range.html).

Fig. 4. An unrooted phylogenetic tree based on the nucleotide sequence of complete or near-complete genomes of all 29 available ZIKVs (as of May 2016). Multiple sequence alignments
were performed, and the unrooted phylogenetic tree was reconstructed, as described in Fig. 1. Two major genetic clusters are indicated: African lineage (green circle disc) and Asian lineage
(orange circle disc). Also, the tree shows that all of the eighteen 2015–2016 American epidemic strains (red circle disc) belong to the Asian lineage. The ZIKV strains used in our phylo-
genetic analysis are listed at the bottom of the tree, with a description in parenthesis of the year, country, host of isolation, and their GenBank accession numbers. Note that the genome
of MR-766 has been fully sequenced by four independent groups, and their nucleotide sequences are not identical, likely because of variations in the cultivation history of the virus.
 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64
4.1. Vector-borne transmission
ZIKV is an arthropod-borne virus (arbovirus) that is transmitted by
mosquito vectors, with two distinct transmission cycles (Weaver et al.,
2016): (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 pre-
sumably transmitted by arboreal mosquitoes from non-human pri-
mates 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 en-
vironment of those endemic areas (Akoua-Koffi et al., 2001; Berthet
et al., 2014; Cornet et al., 1979b; Diallo et al., 2014; Dick et al., 1952;
Fagbami, 1979; Grard et al., 2014; Haddow et al., 1964; Marchette
et al., 1969; McCrae and Kirya, 1982; Weinbren and Williams, 1958).
Also, A. hensilli and A. polynesiensis were suggested to be vectors in the
Yap (Ledermann et al., 2014) and French Polynesia (Cao-Lormeau
et al., 2014; Musso et al., 2014b) outbreaks, respectively. In most
cases, however, their vector competence in ZIKV transmission has not
been fully investigated (Diagne et al., 2015). Based on previous studies
with other mosquito-borne flaviviruses (DENV and YFV), the vector
competence is apparently influenced not only by the genetic variation
in the virus and vector (Gubler et al., 1979) but also by the population
density of the vectors in a particular environment (Miller et al., 1989).
This observation is also likely true for ZIKV (Diagne et al., 2015).
In an urban cycle, the transmission of ZIKV is believed to be mediat-
ed predominantly by two Aedes species mosquitoes: A. aegypti, recog-
nized 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 (ECDC, 2016b). Of these two species,
A. aegypti is considered to be the primary vector associated with ZIKV
outbreaks, as supported by (1) isolating or detecting the virus in a
pool of A. aegypti mosquitoes (Akoua-Koffi et al., 2001; Diallo et al.,
2014; Marchette et al., 1969); (2) showing the susceptibility of
A. aegypti mosquitoes to infection with the virus (Boorman and
Porterfield, 1956; Cornet et al., 1979a; Li et al., 2012); and (3) demon-
strating the transmission of the virus from artificially fed A. aegypti mos-
quitoes to rhesus monkeys and mice (Boorman and Porterfield, 1956).
As a secondary vector for ZIKV, A. albopictus has been suggested to be in-
volved in the urban transmission in Gabon, where five human sera and
two A. albopictus pools collected in an urban setting in 2007 were posi-
tive for ZIKV (Grard et al., 2014), and in Singapore, where high dissem-
ination and transmission rates of ZIKV in local A. albopictus have been
reported (Wong et al., 2013). Because of its high invasive ability and
Fig. 5. Vector-borne transmission of ZIKV. There are two mosquito-driven transmission cycles: (1) a sylvatic cycle, in which the virus cycles between non-human primates and arboreal
mosquitoes; and (2) an urban cycle, in which the virus cycles between humans and urban mosquitoes. Under certain circumstances, ZIKV can presumably be transmitted from non-human
primates to humans via arboreal mosquitoes.
55
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 (Ponlawat and Harrington, 2005; Scott and Takken, 2012) and
are widely distributed throughout the tropical and subtropical regions
of the world, with the habitat of A. albopictus extending further into
cool temperate regions (Kraemer et al., 2015; Paupy et al., 2009;
Thomas et al., 2012). In the US, both A. aegypti and A. albopictus are pres-
ent in practically the entire southern and southeastern half of the coun-
try (Fig. 3, inset map), according to a recent estimate by the Centers for
Disease Control and Prevention (CDC, 2016e), reaching their maximal
abundance in June–October each year (Monaghan et al., 2016). 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) (Chouin-Carneiro
et al., 2016). 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 as-
sociation with humans (Gubler, 2002). Collectively, there is real poten-
tial for the spread of ZIKV across portions of the southern US over the
next few years.
Moreover, ZIKV has been isolated or detected occasionally in other
mosquitoes, such as Anopheles coustani, Culex perfuscus, and Mansonia
uniformis (Diallo et al., 2014; Faye et al., 2013). 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. Fur-
ther 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 trans-
fusion: (i) ZIKV can be passed from an infected mother to her fetus dur-
ing pregnancy, as evidenced not only by the detection of viral RNA in the
amniotic fluid, urine, or serum of mothers whose fetuses had brain ab-
normalities (Brasil et al., 2016; Calvet et al., 2016; Driggers et al.,
2016; Jouannic et al., 2016; Meaney-Delman et al., 2016; Oliveira Melo
et al., 2016; Sarno et al., 2016; Villamil-Gomez et al., 2016), but also
by probing of viral RNA/proteins/particles in the brain, placenta, or
serum of newborns with microcephaly and those aborted (Besnard
et al., 2014; Butler, 2016; Driggers et al., 2016; Faria et al., 2016;
56 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64

Martines et al., 2016; Mlakar et al., 2016; Sarno et al., 2016). (ii) ZIKV
can be sexually transmitted from an infected person to his or her part-
ners, 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 (Armstrong et al., 2016;
Atkinson et al., 2016; Deckard et al., 2016; Foy et al., 2011; Frank et al.,
2016; Freour et al., 2016; Hills et al., 2016; Mansuy et al., 2016; Musso
et al., 2015c; Venturi et al., 2016). In addition to semen, it is important
to note that ZIKV has also been detected in urine, saliva, and nasopha-
ryngeal swabs, potentially facilitating the non-vector-borne transmis-
sion of ZIKV (Atkinson et al., 2016; Barzon et al., 2016a; Besnard et al.,
2014; Brasil et al., 2016; Fonseca et al., 2014; Gourinat et al., 2015;
Korhonen et al., 2016; Kutsuna et al., 2014; Leung et al., 2015; Maria
et al., 2016; Musso et al., 2015b; Musso et al., 2015c; Roze et al., 2016;
Shinohara et al., 2016). (iii) ZIKV RNA/particles have been detected in
breast milk, suggesting a potential risk of viral transmission through
breastfeeding (Besnard et al., 2014; Dupont-Rouzeyrol et al., 2016).
(iv) ZIKV is likely to be transmitted through transfusions of blood
from donors who have been infected with the virus (Aubry et al.,
2015; Aubry et al., 2016; Faria et al., 2016; Musso et al., 2014a).
(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
(Swaminathan et al., 2016). Although these non-vector-borne transmis-
sions of ZIKV are believed to be uncommon, further studies are neces-
sary to identify the risk factors involved in these routes of viral
transmission.
5. Virology
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
(Kostyuchenko et al., 2016; Sirohi et al., 2016). In the case of the
American ZIKV strain PRVABC-59 (GenBank accession no. KX377337)
isolated from a patient in Puerto Rico in 2015 (Lanciotti et al., 2016),
the genomic RNA is 10,807 nucleotides (nt) long and comprises a single
10,272-nt open reading frame (ORF) flanked by a 107-nt 5′ noncoding
region (NCR) and a 428-nt 3′ NCR (Yun et al., 2016) (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 (Kim et al., 2015;
Yun et al., 2016): C (122 aa), prM (168 aa), E (504 aa), NS1 (352 aa),
NS2A (226 aa), NS2B (130 aa), NS3 (617 aa), NS4A (150 aa), NS4B
(251 aa), and NS5 (903 aa). The three N-terminal structural proteins
are necessary for the formation of infectious virions (Kostyuchenko
et al., 2016; Sirohi et al., 2016), and the seven C-terminal nonstructural
proteins are essential for the replication of the viral genomic RNA
(Brinton, 2013; Villordo and Gamarnik, 2009; Westaway et al., 2002;
Yun and Lee, 2006). Viral RNA replication is catalyzed by the two viral
nonstructural proteins: (1) NS3 has an N-terminal serine protease do-
main, which requires NS2B as a cofactor for its activity (Lei et al.,
2016; Phoo et al., 2016); it also has a C-terminal RNA helicase domain
that also possesses nucleoside triphosphatase and RNA 5′-

Fig. 6. Genome structure and replication cycle of ZIKV. (A) A schematic diagram of the ZIKV genomic RNA. The single open reading frame (ORF) encoded in the viral genome is shown as a
long gray barrel, with the three structural (green) and seven nonstructural (magenta) proteins defined below the ORF. NCR, non-coding region. Open arrowheads indicate the cleavage
sites for cellular signalases, and solid arrowheads mark the cleavage sites for the viral serine protease (NS2B-NS3). A gray arrowhead indicates the cleavage site for furin or a furin-like
protease. The cleavage at the NS1-NS2A junction is mediated by an unknown protease(s). (B) Proposed life cycle of ZIKV. The eight major steps of the viral life cycle are: attachment,
endocytosis, membrane fusion, translation, RNA replication, assembly, maturation, and release.
Source: Yun and Lee, 2014.
 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64
triphosphatase activities (Jain et al., 2016). (2) NS5 has an N-terminal
methyltransferase domain (Coloma et al., 2016; Zhang et al., 2016a)
and a C-terminal RNA-dependent RNA polymerase domain (Adiga,
2016; Cox et al., 2015).
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 re-
search (Lindenbach et al., 2013). As schematically illustrated in Fig. 6B,
flaviviruses enter their host cells initially by binding nonspecifically to
the cell surface (Chen et al., 1997; Davis et al., 2006; Navarro-Sanchez
et al., 2003; Pokidysheva et al., 2006; Tassaneetrithep et al., 2003),
followed by internalization specifically through clathrin-mediated en-
docytosis in a viral glycoprotein E-dependent manner (Perera-Lecoin
et al., 2013; Pierson and Kielian, 2013). 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 (Harrison, 2008; Kaufmann and Rossmann, 2011;
Smit et al., 2011; Stiasny et al., 2011). Viral RNA replication takes place
in close association with virus-induced intracellular membrane struc-
tures 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 (Gillespie et al., 2010; Hsu et al., 2010; Welsch
et al., 2009). Assembly of immature virions is initiated by budding of a
viral genomic RNA-C protein complex into the endoplasmic reticulum
(Zhang et al., 2003; Zhang et al., 2007), where it is enveloped by the
lipid bilayer with the viral prM and E proteins embedded (Lorenz
et al., 2002). These immature virions undergo a maturation process
while moving through the host secretory pathway (Mackenzie and
Westaway, 2001) and particularly the trans-Golgi network, going
through post-translational modifications that include the cleavage of
prM by furin or a furin-like protease to produce the mature M protein
(Stadler et al., 1997; Yu et al., 2008). Finally, the completely or partially
mature virions are released from the cell via exocytosis (Pierson and
Diamond, 2012). 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 in-
dividuals who develop a mild and self-limited illness, with an incuba-
tion period of 4–10 days (Bearcroft, 1956; CDC, 2016g; Cerbino-Neto
et al., 2016; Duffy et al., 2009; Lazear and Diamond, 2016; Musso
et al., 2014a). In symptomatic cases, the common symptoms are non-
specific 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 (Brasil et al., 2016;
Cao-Lormeau et al., 2014; Duffy et al., 2009; Macnamara, 1954; Musso
et al., 2014a; Zammarchi et al., 2015a). Other clinical manifestations ob-
served with acute ZIKV infection include hematospermia (Foy et al.,
2011; Musso et al., 2015c), hearing difficulties (Tappe et al., 2015),
thrombocytopenia, and subcutaneous bleeding (Chraibi et al., 2016;
Duijster et al., 2016; Karimi et al., 2016; Sharp et al., 2016). The symp-
toms generally appear along with the viremia and disappear
57
spontaneously within a week, but arthralgia may persist for up to a
month (Foy et al., 2011).
6.2. Guillain-Barré syndrome
Guillain-Barré syndrome is an autoimmune disease in which the im-
mune system attacks part of the peripheral nervous system, causing tin-
gling, muscle weakness, paralysis, and even death (Creange, 2016;
Goodfellow and Willison, 2016). Previously, this neuromuscular com-
plication had been associated with infection by other arboviruses,
such as DENV (Carod-Artal et al., 2013; Ralapanawa et al., 2015;
Simon et al., 2016; Verma et al., 2014) and chikungunya virus
(Wielanek et al., 2007). The temporal and geographic association of
ZIKV with Guillain-Barré syndrome was initially observed during the
2013–2014 outbreak reported in French Polynesia (ECDC, 2014;
Musso et al., 2014b; Oehler et al., 2014) and subsequently during the
2015–2016 outbreak that is still ongoing in the Americas (Broutet
et al., 2016; Roze et al., 2016; Thomas et al., 2016). During the previous
French Polynesia outbreak, the incidence of Guillain-Barré syndrome
was estimated to be ~ 20-fold higher than its basal incidence of 1–2
cases per 100,000 population per year (Oehler et al., 2014; Sejvar
et al., 2011). 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 (Cao-Lormeau
et al., 2016). The same study also showed that patients with Guillain-
Barré syndrome had electrophysiological characteristics consistent
with the acute motor axonal neuropathy type of the disease (Cao-
Lormeau et al., 2016). 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 syn-
drome is unknown but is under active investigation.
6.3. Microcephaly
Microcephaly is a neurological condition in which the brain of a baby
does not develop properly, causing the head to be smaller than normal
(Klase et al., 2016; Panchaud et al., 2016; Tang, 2016). It is divided into
two types: (1) primary or congenital microcephaly, which is present in
utero or at birth; and (2) secondary or postnatal microcephaly, which
develops after birth (Alcantara and O'Driscoll, 2014; Passemard et al.,
2013). While primary microcephaly is likely caused by a decrease in
the number of neurons produced during neurogenesis, secondary mi-
crocephaly is presumably caused by a reduction in the number of
dendritic processes and synaptic connections (Woods, 2004). Micro-
cephaly can be caused by a variety of genetic mutations, peri- and
post-natal brain injuries, teratogenic agents, and congenital infections
(Dahlgren and Wilson, 2001; von der Hagen et al., 2014). Earlier, con-
genital microcephaly had been described in association with rubella
virus (De Santis et al., 2006; Webster, 1998) and cytomegalovirus
(Plosa et al., 2012; Swanson and Schleiss, 2013). For ZIKV, a causal rela-
tionship between prenatal infection and microcephaly emerged in
Brazil, as the number of newborns with microcephaly began to rise in
September 2015 (Microcephaly Epidemic Research Group, 2016;
Schuler-Faccini et al., 2016); thereafter, 8301 cases of microcephaly
were recorded from November 2015 to July 2016 in that country
(Magalhaes-Barbosa et al., 2016). Subsequently, the potential risk of mi-
crocephaly associated with ZIKV infection has been suggested by two
retrospective studies from French Polynesia (Cauchemez et al., 2016;
Jouannic et al., 2016) and one prospective study from Brazil (Brasil
et al., 2016). In addition to this spatiotemporal association, ZIKV or its
gene expression has been detected in the amniotic fluid (Calvet et al.,
2016; Jouannic et al., 2016; Meaney-Delman et al., 2016; Sarno et al.,
2016) and in various tissues of fetuses with microcephaly and those
who died after birth or following abortion (Besnard et al., 2014;
58 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64
Butler, 2016; Driggers et al., 2016; Faria et al., 2016; Martines et al.,
2016; Mlakar et al., 2016; Sarno et al., 2016). Moreover, ZIKV-specific
IgM has been identified in the cerebrospinal fluid and serum of neonates
with microcephaly (Cordeiro et al., 2016; de Araujo et al., 2016).
According to the most recent guideline of the Centers for Disease
Control and Prevention, congenital microcephaly is defined as: (i) for
live births, having a head circumference (HC) at birth below the third
percentile for the age and sex of the baby or, if the HC at birth is unavail-
able, an HC below the third percentile within the first 2 weeks after
birth; and (ii) for stillbirths and elective abortions, having a HC at deliv-
ery below the third percentile for the age and sex of the baby (CDC,
2016c). In general, HC is a good indication of total brain volume that
has been used to evaluate brain growth and size (Barbier et al., 2013;
Bolduc and Shevell, 2005; Sullivan et al., 2014). A significance difference
in brain size is an important risk factor for motor and cognitive dysfunc-
tion (von der Hagen et al., 2014; Watemberg et al., 2002). Accumulated
data on pre- and post-natal clinical cases to date suggest that ZIKV infec-
tion during pregnancy is linked to microcephaly and other congenital
abnormalities (e.g., facial disproportionality, cutis girata, hypertonia/
spasticity, and hyperreflexia), occasionally accompanied by neuroimag-
ing abnormalities such as calcifications, ventriculomegaly, and
lissencephaly (Brasil et al., 2016; Driggers et al., 2016; Hazin et al.,
2016; Meaney-Delman et al., 2016; Microcephaly Epidemic Research
Group, 2016; Miranda-Filho Dde et al., 2016; Mlakar et al., 2016;
Oliveira Melo et al., 2016; Petersen et al., 2016; Sarno et al., 2016;
Schuler-Faccini et al., 2016). Recently, the ZIKV-microcephaly associa-
tion has been supported by a preliminary report of the first case-
control study, showing that 13 of 32 newborns with microcephaly and
none of 62 controls without microcephaly had laboratory-confirmed
ZIKV infection (de Araujo et al., 2016). In addition, congenital ZIKV in-
fection has also been suggested to be associated with hearing loss
(Leal et al., 2016a; Leal et al., 2016b; Miranda-Filho Dde et al., 2016)
and ocular anomalies (de Paula Freitas et al., 2016; Miranda-Filho Dde
et al., 2016; Oliveira Melo et al., 2016; Ventura et al., 2016a; Ventura
et al., 2016b; Ventura et al., 2016c; Ventura et al., 2016d).
6.4. Other neurological complications
Case reports suggest that ZIKV infection may be associated with
other neurological complications, including the case of an 81-year-old
man who developed meningoencephalitis (Carteaux et al., 2016) and
the case of a 15-year-old girl who was diagnosed with acute myelitis
(Mecharles et al., 2016). As research progresses, it is likely that other
neurological and non-neurological complications caused by ZIKV infec-
tion will be identified in the future. Case-control or cohort studies, to-
gether with well-characterized case reports, will be required in order
for us to better understand the potential role of ZIKV infection in adults
and newborns (Musso and Baud, 2016; Rasmussen et al., 2016).
7. Tissue and cell tropism
ZIKV RNA has been detected both in the brains of infants with micro-
cephaly who died and in the placentas of women who had spontaneous
abortion during the first or second trimester because of suspected ZIKV
infection (Bhatnagar et al., 2017). After subcutaneous infection of ZIKV
in a pregnant nonhuman primate (pigtail macaque), viral RNA has
been identified in fetal and maternal tissues, specifically the fetal brain
and liver, the chorionic villi of the placenta, and the maternal brain,
eyes, spleen and liver; of these tissues, the placenta has the highest
viral RNA load (Adams Waldorf et al., 2016). Over the last year, rapid
progress has been made in the development of both human cell-based
in vitro models and in vivo mouse models for the study of ZIKV
neuropathogenesis. To date, it has been demonstrated that ZIKV, al-
though capable of infecting mature neurons, preferentially infects
human neural progenitor cells (hNPCs) and triggers apoptosis
(Onorati et al., 2016; Tang et al., 2016), suggesting a potential
mechanism for microcephaly, since hNPCs drive the development of
the cortex of fetal brains. Consistent with these findings, ZIKV infection
of human brain organoids (three-dimensional cell culture systems reca-
pitulating early events in brain development) led to a reduction in pro-
liferative zones and disrupted cortical layers, thereby causing a decrease
in overall organoid size reminiscent of microcephaly (Cugola et al.,
2016; Dang et al., 2016; Garcez et al., 2016; Qian et al., 2016). In mice
(SJL, ICR, and C57 strains), ZIKV can replicate in the brains of embryos
by targeting different neuronal lineages, causing cell cycle arrest, apo-
ptosis, and inhibition of NPC differentiation, all of which affect the corti-
cal development of the embryos (Cugola et al., 2016; Li et al., 2016; Wu
et al., 2016). Also, intracranial infection of ZIKV in early postnatal C57BL/
6 mice has been shown to deplete proliferating cells in the ventricular
zone of the neural stem cell compartment and destroy corticospinal py-
ramidal neurons, a cell type implicated in ZIKV-induced microcephaly
(Huang et al., 2016). In addition to the direct disruption of NPCs, mature
neurons, and other cells in the brain (Bayless et al., 2016; Dang et al.,
2016), the differentiation and migration of neurons in the developing
brain are also believed to be affected by ZIKV infection. Further studies
are warranted to elucidate the pathobiology of ZIKV-induced brain
malformations and their underlying mechanisms. Furthermore,
in vitro infection studies of human placental cells have shown that mac-
rophages, trophoblasts, and endothelial cells are susceptible to ZIKV in-
fection to various degrees, presumably depending on gestational age
and host genetic variation (Bayer et al., 2016; Quicke et al., 2016;
Tabata et al., 2016).
In human and mouse studies, ZIKV is shown to be able to establish a
productive infection not only in the fetus and placenta during pregnan-
cy but also in the eyes and male and female reproductive tracts.
(1) Eyes: ZIKV has been detected and isolated from human conjunctival
swab samples (Sun et al., 2016). Consistent with this clinical finding,
productive ZIKV infection has been observed in ocular tissues in
Ifnar1−/− mice, as evidenced by the shedding of viral RNA in tears and
detection of viral RNA in the cornea, optic nerve, and ganglion and bipo-
lar cells in the retina (Miner et al., 2016). (2) Male reproductive tract: In
mice, a mouse-adapted ZIKV can infect spermatogonia, Sertoli cells, and
Leydig cells in the testis and epididymis, causing testicular tissue dam-
age that is associated with reduced levels of the sex hormones (testos-
terone and inhibin B) and oligospermia (Chan et al., 2016; Govero
et al., 2016; Ma et al., 2016). Although persistent shedding of ZIKV
RNA in semen has been reported in humans for 6 months after the
onset of symptoms (Barzon et al., 2016b; Mansuy et al., 2016; Nicastri
et al., 2016a), such severe injury on testicular tissue as seen in mice
has not yet been described in humans. (3) Female reproductive tract:
A case report has shown that ZIKV RNA is detectable in human cervical
mucus at 11 days after symptom onset, while it is undetectable in blood
and urine samples (Prisant et al., 2016). Another case report has also
shown that ZIKV RNA is present in human vaginal mucosal specimens
for over 11 weeks (Murray et al., 2017). An in vitro infection experiment
has indicated that human uterine fibroblasts are susceptible to ZIKV in-
fection, potentially contributing to the heterosexual transmission of
ZIKV in women (Chen et al., 2016). Overall, ZIKV appears to have a
broad tissue tropism, infecting a wide range of cell types. Therefore, an
important area of ZIKV research in tissue/cell tropism is the identifica-
tion of host factors that promote or restrict viral replication.
8. Conclusion
ZIKV, first isolated in Uganda in 1947, is transmitted among people
primarily by the bite of infected Aedes species mosquitoes
(e.g., A. aegypti and A. albopictus) or secondarily through non-vector
modes (i.e., vertical transmission, sexual transmission, and blood trans-
fusion). ZIKV was confined to Africa and Asia for over half a century after
its discovery, before it emerged in the Pacific Islands by the late 2000s
and early 2010s. Now it has gained a major foothold in the Americas
and is poised to jump to the rest of the world. From a clinical standpoint,
 B.-H. Song et al. / Journal of Neuroimmunology 308 (2017) 50–64
ZIKV infection was considered to be associated only with mild nonspe-
cific flu-like illness prior to the 2013–2014 French Polynesian outbreak,
when serious neurological complications were reported, and the
2015–2016 American outbreak, when severe congenital malformations
were documented. The most worrying aspect of ZIKV infection is that
we do not yet know the real scope of its complications, which may be
more far-reaching than those initially anticipated. Much more research
effort is required to fill the knowledge gaps concerning ZIKV pathogen-
esis and to develop medical countermeasures against this previously
neglected but newly emerging human pathogen.
Acknowledgments
This work was supported by the Utah Science Technology and
Research Initiative (USTAR A34637 and A36815) and by a grant
(200784-00001) from the American Board of Obstetrics and Gynecolo-
gy, the American College of Obstetricians and Gynecologists, the
American Society for Reproductive Medicine, and the Society for Repro-
ductive Endocrinology and Infertility. We thank Dr. Deborah McClellan
for her careful and critical reading of our paper. There is no conflict of in-
terest in this paper.
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