Received: 16 July 2017

|
DOI: 10.1002/jobm.201700398
Revised: 19 September 2017
| Accepted: 3 September 2017

REVIEW

Zika virus: what we need to know?

Farakh Javed1 | Khanzadi N. Manzoor1 | Mubashar Ali1 | Irshad U. Haq1 |

Abid A. Khan3 | Assad Zaib2 | Sobia Manzoor4

1 Department of Microbiology, University

of Haripur, Haripur, Pakistan
2 Department of Medical Lab Technology,
University of Haripur, Haripur, Pakistan
3 Department of Biosciences, COMSATS
Institute of Information Technology,
Islamabad, Pakistan
4 Atta-ur-Rehman School of Applied Bio-
Sciences, National University of Science
and Technology, Islamabad, Pakistan
Correspondence
Farakh Javed, Department of Microbiology,
University of Haripur, Haripur, Pakistan.
Email: farukhbbt@gmail.com;
farakh.javed@uoh.edu.pk
Zika virus is one of the emerging viruses and is of significant threat to human health
globally. It is a mosquito borne flavivirus similar to dengue, yellow fever, and West
Nile viruses. It was reported about 5 decades ago and then it spreads to different parts
of the world. Large outbreaks were reported on Yap Islands in 2007. Now it has
gained wide attention globally by health communities. Major vector for virus
transmission is Aedes aegypti mosquito. ZIKV infection is mostly asymptomatic but
it is also responsible to cause mild influenza like illness to serious manifestations.
There is no specific anti-viral treatment is available for ZIKV infection. The virus
disseminates very fast due to which it possesses a serious threat especially in those
areas where there is lack of specific immunity against virus. Little knowledge is
available on its transmission and pathogenicity. Although virus was discovered years
ago but its genomic structure is not clearly understood yet. In this review we focus on
the current knowledge of epidemiology of ZIKV, its transmission, its structural
biology, different aspects of diagnosis and diagnostic challenges as well as
highlighted appropriates antiviral drugs and vaccines regarding treatment.

KEYWORDS
Aedes aegypti, genetic variability, non-structural proteins, Zika virus

1 | INTRODUCTION
Zika virus is an Arbovirus first time discovered in 1947 from
the forest of Uganda named Zika. After 1 year it was also
isolated from a mosquito specie Aedes africanus. This virus
belongs to the genus Flavivirus and family Flaviviridae,
which includes 52 other viral species i.e. the yellow fever,
dengue, West Nile viruses, and Saint Louis encephalitis [1,2].
Virions of Flavivirus family are spherical in shape with a
ssRNA genome. This family genome has 3′ and 5′
untranslated regions and polyprotein coding single open
reading frame [3].
Diseases that are spread by Aedes mosquito like ZIKV,
dengue and chikungunya infections are of great risk for
humans. Extensive knowledge is available about the biology
of these vectors and their role in the transmission of diseases
J Basic Microbiol. 2018;58:3–16.
but still are major reason of causing mortality in tropical and
subtropical regions around the globe [4]. In Nigeria first
human infection of ZIKV was reported in 1954 [5]. Later on
viral incidence in some Asian countries including Pakistan,
Malaysia, Indonesia, Cambodia, and Micronesia were also
reported [6–10]. ZIKV widely spread in Southeast Asia and
Africa between human and non-human primates reser-
voir [8,9,11]. After 2–3 days incubation period symptoms
usually starts with mild headache and then followed by rash,
fever, joint pain along with some other manifestations like
diarrhea, constipation, and abdominal pain [9]. No vaccines
are available for ZIKV infection in the market however there
are currently 45 candidates are in trial phase. Some preventive
measures can help in reduction and elimination of infec-
tion [12]. However more work need to be done to find exact
number of complications caused by ZIKV.
www.jbm-journal.com © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim | 3
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| JAVED ET AL.

2 | HISTORY AND OUTBREAKS
In 1947 the virus was first isolated from monkey and then
successfully purified from a mosquito named Aedes africanus
in 1948 [2]. Confirmation of first human infection was made
in 1952 by the help of serological studies [13]. Then it was
discovered that the virus cause sporadic infections in humans
throughout Africa and Asia. Presence of ZIKV in Indian
subcontinent was reported by the detection of viral antibodies
among different subjects in Bharuch district in 1954 [14]. In
Nigeria first human infection of ZIKV was reported in
1954 [5]. Virus was isolated from Aedes aegypti obtained
from Malaysia in 1966 and that time virus was first detected in
Asia along with the evidence of virus transmission by an
urban vector [6]. In Asia first human infections were
diagnosed after 11 years in Java and then in Indonesia where
seven patients showed symptoms of fever, anorexia, malaise,
dizziness, and stomach ache [7]. Viral antibodies were also
detected from healthy people in Pakistan, India, and
Egypt [14–16]. In 2007 outbreak of ZIKV was reported in
Yap Island in which about 75% of population was infected
within 4 months, while in 2010 in Cambodia ZIKA infection
was reported. In 2012 ZIKV outbreak occur in Philippines
and then in Thailand from 2012 to 2014 [8,10,17–19]. In 2013
ZIKA outbreak was reported in pacific oceans of French
Polynesia and this time ZIKV cause serious infection,
accompanied by dengue epidemic. That outbreak ZIKV
targeted approximately 29,000 people in which 72 cases
showed severe symptoms [20–22]. After that epidemics
spread to some other islands i.e. New Caledonia, Vanuatu, the
Cook Islands, and the Solomon Islands [23,24]. In early 2014
the first autochthonous outbreak with fifty-one cases was
reported on Easter Island [25]. Transmission of virus in Brazil
was confirmed by Brazilian Ministry of Health in 2015, with
first case identification in northeast region of the coun-
try [26,27]. Transmission of virus to 29 other American
countries was reported in 2016 [28]. World map show the
ZIKV infected areas in (Fig. 1). In Brazil most recent outbreak
started in 2015, with total number of infections more than 1.5
million, known to be the largest outbreak of human history of
ZIKV [29]. In America 559,721 cases of ZIKV with 209,628
laboratories confirmed cases have been reported in
April 2017. Ninteen cases of ZIKV infection had been
reported among Korean travelers in May 2017. Taiwan
Ministry of Health and Welfare reported 14 cases of ZIKV
infection as of May 2017. In Singapore from January 2017 till
June 2017, 38 positive cases have been reported and 13
positive cases in Vietnam during first 2 months of 2017 [30].

FIGURE 1 World map showing the most common outbreaks of ZIKA. ZIKA virus had observed in parts of Africa and South East Asia, but
since 2007 onward there have been various outbreaks outside these regions and spread to various other countries in different years
JAVED ET AL.
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Public Health Emergency of International Concern was aegypti. The bacterium could present a novel biological control
declared by World Health Organization in mechanism, aiding efforts to stop the spread of Zika virus [43].
February 2016 [31].
4 | ZIKV VARIABILITY AND
SEQUENCE ANALYSES
3 | VECTORS AND TRANSMISSION
ZIKV genome shown incredible sequence variation because of
The major vector of ZIKV in Asia is a mosquito Aedes
the lack of proofreading activity of the NS5B RdRp.
aegypti [7]. The second important vector for virus transmis-
Computational analysis of the nucleotide sequences of NS5
sion that originate from Asia named Aedes albopictus, that
genes of ZIKV total four ZIKV lineages i.e. Asian, West
range extended worldwide within last decades [32]. Nowa-
African, East African, and American have been identified [3,44].
days both species persist in various Asian and American
In addition to genotypes, ZIKV exists inside its hosts as a pool of
territories [33]. Currently ZIKV has also been isolated from
genetically distinct but closely related variants referred to as
Aedes furcifer, Aedes vittatus, Aedes taylori, and from Aedes
quasispecies as shown in Fig. 2. The relationship between ZIKV
hirsutus [34]. Mosquito get infection when it bites to an
sequence variability and resistance to current treatment is
infected person and then a transmission cycle developed
unclear [45]. Currently the intensive sequence of ZIKV genome
between human and mosquito. There are main four
is conducted and nearly 840 ZIKV sequence including 35 full
transmission sources of ZIKV have been reported till now
length genome deposited so far in generic data banks (Genbank,
i.e. i) through mosquito bites; ii) human to human
European Molecular Biology Laboratory [EMBL], and DNA
transmission; iii) through blood transfusion; and iv) animal
Data Bank of Japan [DDBJ]) [26].
to human transmission [35]. Antigens and antibodies against
these viruses have been isolated from various nonhuman
primates that showing animals also as reservoir for this virus 5 | GENOME ORGANIZATION
(Table 1) [36]. The infected female mosquito usually transmit
the virus through its bite but perinatal transmission of virus ZIKV has a positive-sense single-stranded RNA (+ssRNA)
has been also reported [37]. Viral RNA and/or proteins have genome with approximately 11 Kb in size (Fig. 3) [3]. It
been detected in amniotic fluid and placental tissues that contain single open reading frame with untranslated regions
are transparent evidence of several other transmission (UTR) at 3′ and 5′ ends [46]. The diameter of the virion is
modes [38,39]. approximately is 50–60 nm while its nucleocapsid arranged in
Virus presence also reported in human semen that indicate icosahedral symmetry [47,48]. Polypeptide protein of ZIKV
the viral transmission via sexual route [40]. Hamer et al. [41] is divided into three structural and seven non-structural
also reported male-to-female, female-to-male, and male-to- proteins (Table 2).
male sexual transmission of ZIKV. Blood transfusions are
found the main reason of viral transmission after confirmed
5.1 | Structural proteins
cases reported in Brazil. ZIKV infection of primary human
placental macrophages and placental villous fibroblasts had
5.1.1 | Capsid (C) protein
been demonstrated in a study [42]. Wolbachia pipientis, a gram
negative bacterium that infects arthropods including insects, Capsid (C) protein is made up of 122aa. It is present in the
can completely block the transmission of Zika virus in Aedes cytoplasm of the infected cells while form a nucleocapsid

TABLE 1 Animal host of the ZIKA virus

Sl. No. Animals Area Year Citation
1. Rhesus, monkeys Zika forest, Uganda 1947 [2,13]
2. Bwamba county monkeys Uganda, Bwamba country, Zika forest 1969 [149]
3. Duck, goat, cow, horses, bats, rats Lombok, Indonesia 1978 [150]
4. Wild mammals monkeys Ethiopia, Senegal 1967–1968 [151]
5. Monkeys Gabon 1982 [152]
6. Rodents, domestic sheep, goats Pakistan 1983 [15]
7. Wild orangutans Malaysia, Borneo 1997 [97]
8. Monkeys Senegal 1962–2008 [153]
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| JAVED ET AL.

FIGURE 2 Evolutionary relationships of taxa. The evolutionary history was inferred using the Neighbor-Joining method. The optimal tree
with the sum of branch length = 0.27860208 is shown. The percentage of replicate trees in which the associated taxa clustered together in the
bootstrap test (1000 replicates) is shown next to the branches. The tree is drawn to scale, with branch lengths in the same units as those of the
evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Maximum Composite Likelihood
method and are in the units of the number of base substitutions per site. The analysis involved 35 nucleotide sequences. Codon positions
included were 1st + 2nd + 3rd + Noncoding. All positions containing gaps and missing data were eliminated. There were a total of 1096 positions
in the final dataset. Evolutionary analyses were conducted in MEGA5
JAVED ET AL.
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FIGURE 3 Genome of Zika virus. Zika possess +ssRNA with an open reading frame about 10 kb, encoding three structural protein C, prM,
and E and seven non-structural protein NS1–NS5 were colored in purple, green, and blue, respectively. The lengths of the encoding proteins
were indicated. Red arrow, black arrow, and purple arrow indicate the cleavage site of viral NS2B/NS3 protease, signal peptidase, and Golgi
protease, separately. The light brown arrow indicates an unknown host protease

complex with RNA in viral particle. All capsid proteins of the 5.1.3 | Envelope (E) protein
virion have positive net charge and are similar in size but with
Envelope (E) protein having 500aa, that encodes the
minor sequence conservation [49,50]. This protein is released
envelope, C protein, and prM protein (which is a precursor
into the cytosol and assembles homodimers after polyprotein
of the membrane) [56]. E protein performed function with
cleavage. One side domain of the capsid protein contains the
surface protein that plays a vital role in binding and membrane
basic residues that bind with the RNA genome while other
fusion process [57]. The E protein is divided into three
side domain contains hydrophobic residues that cooperate
domains. Domain I concerned in the organization of envelope
with the lipid envelope of the virus [51,52]. After endosomal
structure while domain II and III involved in receptor binding
membrane fusion of the virus, viral genome entering remains
and monomer interaction respectively [3]. E protein is
related with the C dimers to evade RNA sensors and nucleases
responsible for targeting the receptors of the host cell and fuse
from the host. In addition to role in the synthesis of viral
the virus and cell membranes to permit the entry of the virus.
nucleocapsid, C protein functions as RNA chaperone. Thus,
Usually major target for antibodies is E protein but in case of
resulting nucleocapsid buds formation in the lumen of
dengue, it generate antibodies against the prM protein [58].
endoplasmic reticulum to make viral particles with E and prM
proteins [53,54].
5.2 | Non-structural proteins
5.1.2 | Pre membrane (PrM) protein ZIKV genome encoding seven non-structural (NS) proteins
i.e. NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5.
Pre membrane (PrM) protein is made up of 178aa, which is
buried under the layer of E-protein. The M and E proteins are
5.2.1 | NS1
arranged in icosahedral symmetry consisting of repeating 60
units, and each of asymmetrical unit comprise of three NS1 protein is extremely preserved protein with the
individual E-proteins [55]. molecular weight of 46–55 kDa and about 342aa long
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| JAVED ET AL.

TABLE 2 Structural and non-structural proteins of ZIKA virus [47–49]

Proteins name Symbol Size (aa) Location in cell Function in cell
Structural
Capsid C 122 Cytoplasm Viral nucleocapsid formation
Pre membrane prM 178 Cytoplasm Viral capsid formation, host cell fusion, and stabilization
Envelop E 500 Cytoplasm Host receptor binding, fusion, and entry
Non Structural
NS1 protein NS1 384 Cytoplasm Emission, virulence, and replication
NS2 protein NS2A 226 Cytoplasm Viral transcription and assembly
NS2 protein NS2B 130 Cytoplasm NS3 cofactor for serine protease function, polyprotein cleavage
NS3 protein NS3 617 Cytoplasm Unwinding of structured protein template region and processing of viral
polyprotein via serine protease, helicase and triphosphatase activity
NS4 protein NS4A 127 Cytoplasm Viral replication
NS4 protein NS4B 252 Cytoplasm Viral replication complex
NS5 protein NS5 902 Cytoplasm RNA replication via RNA dependent RNA polymerase and RNA capping

depends on the level of glycosylation. The glycosylation of
NS1 is significant for effective emission, virulence, and
replication of virus [59,60]. NS1 lives as a monomer, a dimer
(a membrane-bound protein, mNS1) and as a hexamer (a
secreted protein, sNS1). TLRs is initiated by NS1 that
slowdown the complement system [61]. Homo dimer of NS1
plays a key role in replication of virus while membrane-bound
NS1 is secreted for provoking immune responses [62,63].
5.2.2 | NS2A
NS2A is 226aa long protein and is multifunctional,
membrane-associated hydrophobic protein that involved in
replication of RNA [64]. NS2A protein binds with
3′-untranslated region of RNA virus and to other replication
complex [65]. Furthermore, NS2A plays a role in controlling
the antiviral interferon of the host response and secretion of
viral particles from cell [66,67].
5.2.3 | NS2B
NS2B protein is made up of l30aa. This protein is
hydrophobic with partly recognized functions while its
enzymatic motifs are unknown. Two or more membrane-
spanning regions are present in this protein and play central
role in the association and complexes of virus replication on
the endoplasmic reticular membrane [65]. NS2B collaborates
with the C-terminal protease domain of NS3 to make the
complex of serine protease that is involved in the viral
polyprotein cleavage [68].
5.2.4 | NS3
NS3 protein is made up of 617aa. Multi-domain NS3 protein
has C-terminal portion comprising the RNA triphosphatase
(NS3RTPase), RNA helicase (NS3Hel), and an N-terminal
NS3Pro activities involved in capping and RNA synthesis of
the virus [69]. NS3 consists of helicase/NTPase and protease
domain that are involved in the unwinding of structured
template regions and processing of viral polyprotein during
viral RNA synthesis, respectively.
5.2.5 | NS4A
NS4A is made up of 127aa. NS4A protein in Zika virus serves
as determinant factors for pathogenesis of virus and
mechanism of action recognition of its effects [70].
5.2.6 | NS4B
NS4B protein is about 252aa long and poorly conserved
protein. Multiple potential membrane spanning hydrophobic
regions is present in NS4B. Membrane constituents of the
viral replication complex are formed by NS4B and is involved
in localization in membranes of NS3 protein [71].
5.2.7 | NS5
NS5 protein is made up of 902aa, which comprises two
domain one is C-terminal RNA-dependent RNA polymerase
(NS5 RdRp) while second is N-terminal methyltransferase
(NS5MTase). (+)ssRNA viral genome serves as a
template for the synthesis of the intermediate (−)ssRNA
strand by the NS5 RdRp, which acts as template solely for the
synthesis of (+)ssRNA genomic RNA and synthesis of the
viral polyprotein [72,73]. The role of others 3′ NCR region of
the viral genome has been suggested in the viral and cellular
factors recognition, stabilization of the genome, the transla-
tion process, and RNA packaging [74].
JAVED ET AL.
6 | PATHOGENESIS AND CLINICAL
MANIFESTATIONS
Very little information exists on the pathogenesis of ZIKV.
Most (∼80%) of individuals infected by ZIKV are asymp-
tomatic [75]. ZIKV infections have been linked to the
following complications.
6.1 | General symptoms
Symptoms appear within 3–11 days of the mosquito
bite [76,77]. These usually start with mild headache followed
by maculopapular rash (neck, face, trunk, and upper arms, and
spread to palms and soles), fever, malaise, conjunctivitis, and
joint pains along with some other manifestations that include
diarrhea, constipation, abdominal pain, anorexia, dizziness,
and conjunctivitis. Rashes are not the uniform feature of this
disease [9]. Less frequent manifestations include myalgia,
vomiting, edema, and retro-orbital pain [78]. Infection caused
by ZIKV sometimes resembles a mild form of dengue
fever [79]. Viral RNA can be detected from serum within 0–
11 days after the onset of symptoms [9,80]. Susceptibility of
human skin cells to ZIKV infection is showed by in vitro and
ex vivo experiments, including dermal fibroblasts, epidermal
keratinocytes and immature dendritic cells [48]. Coffey
et al. [81] reported that ZIKV has a wide range of tissue
tropism i.e. it infects the hemolymphatic system, spleen,
lymph, nodes, gastrointestinal, integument, cardiopulmonary,
genitourinary system, spinal cord, and cerebrospinal fluid.
ZIKV infection has been also reported in kidney, bladder and
execrated urine, while in males ZIKV can infect the testes,
prostate and seminal vesicles [82,83]. Hirsh et al. [84]
demonstrated that ZIKV also infects the female reproductive
system i.e. it maintained in the vagina, uterus while Miner and
Diamond [85] have shown its presence in vaginal epithelium
and uterine fibroblasts of mice. ZIKV appears to be formed
within the endoplasmic reticulum network in close associa-
tion with membranes of host cell similar to that of other
Flaviviruses, but nuclei of infected cells also contain ZIKV
antigens [48,71,86].
6.2 | Neurological manifestations
Susceptibility to virus with intracerebral inoculation in mice
regardless of the animal age has been demonstrated from
experimental studies. From intraperitoneal route inoculation
infection occurs in mice with the age younger than 2 weeks.
With intracerebral inoculation mice suffered from encephali-
tis with cellular infiltration, neuronal degeneration, and areas
of softening along with enlargement of astroglial cells and the
destruction of the pyriform cells of Ammon'shorn in the
brains [13,86].
| 9
6.3 | Congenital Zika syndrome
According to the previous studies and reports presence of
ZIKV specific IgM in neonates is one of the main reasons of
microcephaly. Viral RNA in amniotic fluid samples has been
found in two pregnant women whose fetuses were diagnosed
with microcephaly. In placental tissue from miscarriages and
in fetal brain tissues from fetus/infants with microcephaly the
RNA and antigens of virus have also been ob-
served [38,39,87]. ZIKV infection diverts a key protein
(phospho- TBK1) necessary for neural cell division in the
developing fetus, thereby causing birth defect microcephaly.
It had been suggested that ZIKV virus might be susceptible to
existing antiviral drugs that may prevent disruption to the
developing nervous system [88].
7 | DIAGNOSIS
7.1 | Serological tests
Upon the appearance of symptoms, diagnosis of ZIKV
infection can be done with the help of several laboratory
parameters and symptoms, for example, gamma-glutamyl
transferase, leukopenia, serum lactate dehydrogenase, throm-
bocytopenia, and elevated protein markers (C-reactive
protein, fibrinogen, and ferritin). The major challenges in
virus detection are absence of specific and sensitive
laboratory tests, some previously reported tests are difficult
to perform as well as some shown cross reactivity. Although,
highly recommended method is PCR based testing of saliva,
blood, and urine, but most of the times the desired amount of
nucleic acid in different body fluids is unavailable [71,89,90].
As ZIKV, dengue and chikungunya have similar symptoms
therefore acute samples are used for molecular diagnosis.
Serological tests are applied on samples that are collected 5–6
days after onset of symptoms. Reverse transcription (RT)-
PCR is a test of choice of acute-phase serum samples. If
genetic material disappears from serum then viral RNA is
detected from patient urine samples with the help of RT-PCR
because viruria lasts for more time than viremia [11,91,92].
Munjal et al. [93] highlighted that after viremia decline and
patient is no more infectious to mosquitos but still they remain
infective to other human hosts with low infection rate.
7.2 | Nucleotide acid amplification tests
The “pan flavivirus” amplification technique combined with
sequencing data is an alternative method to RT-PCR
[3,11,94,95]. Another useful diagnostic approach is real
time RT-PCR (rRT-PCR) [78]. Real-time RT-PCR is an
interesting option as a rapid, sensitive, and specific method
for detection of ZIKV in the early stage of infection. A one
step rRT-PCR for ZIKV which can detect a wider genetic
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| JAVED ET AL.

diversity of ZIKV isolates from Asia and Africa were
described in a study. This assay is a useful tool for detection of
ZIKV infection in regions where a number of other clinically
indistinguishable arboviruses like dengue or chikungunya co-
circulate [96]. Isolation of virus is most beneficial from those
samples that are collected up to 5 days onset of symptoms.
With reference to immunoassays the more specific test is the
plaque reduction neutralization test (PRNT) by neutralizing
antibody that appears within 5 days after onset of disease, but
cross-reactive results in case of secondary flavivirus
infections is its major drawback. Within 3 days of onset of
illness immunoglobulin (Ig) M to ZIKV can be detected with
the help of ELISA [9]. Rapid and sensitive loop-mediated
isothermal amplification (LAMP) assay have been developed
that distinguishes Zika viruses of Asian and African lineages.
The assay conditions allowed the direct detection of Zika
virus RNA in cultured infected cells without the need of RNA
isolation or reverse transcription [97]. For rapid identification
of Zika virus an isothermal nucleic acid amplification test
(NAAT) plays a very important role. This method displayed
high level of sensitivity for Zika virus RNA. This method is
very cost effective and compatible with portable instrumen-
tation, enabling near patient testing and field use [98].
Detection of viral RNA during acute infection using nucleic
acid amplification tests provides more specific results [99].
8 | TREATMENT AND PREVENTION
ZIKV infections become more complicated due to unavail-
ability of reliable vaccines, active prophylactics, and effective
therapeutics. Currently there is no approved drug existing for
the treatment of ZIKV infection but different numbers of anti-
ZIKV vaccines candidates include inactivated virus, nucleic
acid-based vaccines, live vector vaccines, subunit vaccines,
recombinant ZIKV and virus like particles are in clinical trials
(clinical phase I) (Table 3) [93]. For controlling fever and pain
fluids use as well as use of acetaminophen (paracetamol) or
dipyrone is recommended. Aspirin and other anti-inflamma-
tory drugs are not recommended because of having the risk of
bleeding complications. Different repurposed therapeutic
agents and effective compounds and few drugs are in tested
phase for the treatment of ZIKV infections [35]. FDA
approved different effective nucleosides inhibitors (Sofosbu-
vir, 20-C-methylated nucleosides, 7-deaza-20-C-methylade-
nosine, 20-C-ethynyl analog of 50-triphosphates, 20-fluoro-
2-C-methyl-UTP, and Active metabolite) have been
found effective against ZIKV by causing premature termina-
tion of RNA synthesis, viral receptor and entry inhibi-
tion [83,100–103]. Type I interferons- IFN-α and IFN-β, IFN-
λ1, and IFN-α, β, γ have been also found effective as antiviral
defense systems that inhibit the ZIKV replication [104–106].
Varghese et al. [107] reported that Obatoclax mesylate is a
small molecule pan-Bcl-2 antagonist inhibit the viral entery to
host cell by creating acidic environment in endolysosomal
vesicles.
Neutralizing antibodies (mAb 2A10G6 to FLE region,
mAb Z23 and Z3L1, mAb ZIKV-117 to E region, mAbto E
proteindimer-dimer interface, mAb C10- against E region)
are also in trials phase to reduce ZIKV infection and
inhibit its replication [108–110]. On the other side
repurposing drugs (Niclosamide, Emricasan, Seliciclib,

TABLE 3 Vaccines for ZIKA virus under process and clinical trials
Technology Target Developer/Institution Status Citation
Live attenuated ZIKV Whole virus US NIH Pre-clinical [142,143]
DNA vaccine prM-E NIH Vaccine Research Center 1 [144]
DNA vaccine prM-E GeneOne Life Sciences 1 [145]
DNA vaccine prM-E NIH Vccine Research Center 1 [146]
Inactivated virus vaccine Whole virus WRAIR/NIAID 1 [146]
Viral vectors (measles) E Themis Biosciences 1 [147]
mRNA vaccine PrM-E Moderna Therapeutics 1/2 [148]
Inactivated purified vaccine PrM-E Bharat Pre-clinical
Inactivated purified vaccine VLP-DNA Bio-Manguinhos/Fiocruz Work initiated
Inactivated purified vaccine Live dengue recombinant Butantan Work initiated
DNA plasmid expressing VLP Live recombinant adenovirus US CDC Work initiated
Purified inactivated virus Whole virus NewLink Work initiated
Nanoparticles E Novavax Work initiated
Inactivated purified vaccine prM-E Valneva Work initiated
Inactivated whole virus Whole virus BIDMC 1
JAVED ET AL.
Mycophenolic acid, Bortezomib, PHA-690509, Vermec-
tin, Sertraline, Daptomycin, Cyclosporine A, Azathio-
prine, Vinblastine, Vincristine, Nocodazole, Sunitinib,
Clemastine, Colchicine, Azithromycin, Sinefungin, Sur-
amin, Memantine, Kitasamycin, 6-azauridine, Mycophe-
nolic acid etc.) are also considered best remedies to inhibit
ZIKV infection [111–128]. Herbal therapies have been
proved to be a very good strategy to combat ZIKV
infection. Different studies reported that Alternanthera
philoxeroides, Andrographispaniculata, Azidarachtaind-
ica, Euphorbia hirta, Eupatorium perfoliatum, Tinospor-
acordifolia, and Psidiumguajava have broad spectrum
antiviral activity [129–134]. NS2B-NS3 protease is ex-
pressed by ZIKV which basically consists of NS2B
cofactor and NS3 protease domain that is necessary for
the cleavage of ZIKV polyprotein precursor and formation
of fully functional viral proteins. Enzymatic characteriza-
tion of ZIKV protease had been reported and structural
scaffolds for allosteric small-molecule inhibitors had been
identified in a study. From molecular modeling of protease
inhibitor complexes it had been suggested that these
compounds have ability to bind to druggable cavity in
NS2B-NS3 protease interface and then affect productive
interactions of protease domain to its cofactor [135].
Another study reported the discovered antibodies
isolated form different subjects in Mexico and Brazil
that block ZIKV from initiating an infection. Clones of
memory B cells that express immunoglobulin VH3-23/
VK1-5 genes have expended in these subjects by high
ZIKV neutralizing antibody titers. These recurring anti-
bodies neutralize ZIKV and protect against infection [136].
Another study had been shown in a study that broadly
neutralizing activity if ZIKV-immune sera identifies a
single viral serotype. That Zika infection is caused by
one virus serotype may have implications for vaccine
development [137].
Elimination of mosquito vector is the most appropriate
control measure to prevent this infection. The control
strategies that are previously applied for the eradication of
Aedes aegypti proved inefficient. Mosquito population can be
controlled by using bacterium Wolbachia and transgenic
Aedes aegypti along with insecticide spraying. Use of
personal protective measures and repellents are recom-
mended to avoid the bite of mosquito. To reduce the contact
of mosquito vector with humans some other control measures
are the use of window and door nets and the elimination of
potential breeding sites. In the case of pregnant women there
are certain suggestions that include proper symptoms
assessment of ZIKV disease, the laboratorial diagnosis
during the prenatal care, fetus evaluation for brain anomalies
including microcephaly and intracranial calcifications, as
well as special attention on the prevention of mosquito bites
and possibility to sexual transmission of ZIKV [12].
| 11
9 | ZIKA VIRUS AND HEALTH
COMMUNICATION IN THE
21ST CENTURY
A recent study examined the effective use of the social media
site Facebook as an information source for the Zika virus
pandemic. It was found that the misleading posts were far
more popular than the posts dispersing accurate, relevant
public health information about the disease [138]. Zika-
related Twitter incidence peaked after the World Health
Organization declared an emergency. A computational
content analysis identified five themes from Zika-related
Twitter content: i) societal impact of the outbreak; ii)
government, public, and private sector, and general public
responses to the outbreak; iii) pregnancy and microcephaly:
negative health consequences related to pregnant women and
babies; iv) transmission routes; and v) case reports. User-
generated contents sites were preferred direct information
channels rather than those of the government authori-
ties [139]. The two most popular photo-sharing social media
platforms among young individuals are Pinterest and Insta-
gram. Differences between Instagram and Pinterest in
relaying photographic information regarding Zika virus
were assessed in a study. Specifically, in that study it was
investigated whether the percentage of Zika-virus-related
photos with Spanish or Portuguese texts embedded therein
was higher for Instagram than for Pinterest and whether the
contents of Zika-virus-related photos shared on Pinterest were
different from those shared on Instagram. Both photo-sharing
platforms were similar for Zika virus prevention
communication [140].
10 | ZIKA VIRUS, URBANIZATION,
AND GEOGRAPHIC EXPANSION
By 2050, 70% of the world's population will live in cities, and
90% of this urban growth will take place in developing
countries. Zika virus has increased its importance during
recent decades because of human population expansion and
activities that have increased exposure to infection. Zika virus
circulates widely in Africa and Asia, probably using NHPs as
enzootic hosts, and recently caused an epidemic of febrile
illness, apparently involving human amplification, on Yap
Island in the Pacific [141]. The Zika virus was first discovered
in 1947 and has emerged as a global public health threat over
the last decade. The first major outbreak outside of Africa
occurred in 2007 in the Yap Islands of Micronesia, with
another large outbreak in 2013 in French Polynesia. The
geographic spread of the virus accelerated during the last
5 years. The World Health Organization (WHO) predicts that
millions of cases of ZIKV are likely to occur in the Americas
during the next 12 months. Illness is characterized by an
12
| JAVED
incubation period of 3–12 days. Most of the individuals
(∼80%) remain asymptomatic after contracting the virus.
When symptoms developed these are usually mild and self-
limiting. To better identify cases and manage the current and
future outbreaks of ZIKV more accurate and inexpensive
point-of-care testing is required. Given the rapid geographic
spread of ZIKV in recent years, a coordinated local, regional,
and global effort is needed to generate sufficient resources
and political traction to effectively stop further expansion of
the current outbreak. In a recent statement, the World Health
Organization (WHO) confirms that ZIKV is “spreading
explosively” and that the associated level of concern is
“extremely high” [75].
11 | CONCLUSION
ZIKV recent infections in the world highlighted its
epidemiological importance and disease has gained
international importance. Surveillance programs for proper
detection of virus in vectors are needed so as to minimize
its future outbreaks. In addition to this, proper diagnostic
tools are needed to identify ZIKV infection. Flaviviruses
are mostly vaccine-preventable. Live attenuated vaccines
are available for yellow fever and dengue virus infections.
No specific treatment has been approved for ZIKV
infections. Many antiviral compounds and vaccine candi-
dates are in trial phases to overcome the disease. Scientists
are getting closer to manufactured ZIKV vaccine and
methods for effective vector control. There is need to
encourage developing countries to participate in surveil-
lance programs for disease monitoring to stop the ZIKV
epidemics near future.
CONFLICTS OF INTEREST
The authors have declared no conflict of interest.
ORCID
Farakh Javed http://orcid.org/0000-0003-1305-7834
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How to cite this article: Javed F, Manzoor KN, Ali
M, et al. Zika virus: What we need to know?
J Basic Microbiol. 2018;58:3–16.
https://doi.org/10.1002/jobm.201700398