Zika virus is a single-stranded RNA virus belonging to the Flavivirus genus and the Flaviviridae family.
The virus exists in two phylogenetic types: Asian and African.
Most Zika virus infections are mild and self-limiting, but it is a reportable illness.
Zika virus is primarily transmitted by the bite of female Aedes aegypti and Aedes albopictus mosquitoes.
Other transmission methods include sexual contact, blood transfusion, organ transplantation, and perinatal transmission from mother to fetus.
The virus is related to other arboviruses like Japanese encephalitis virus, West Nile virus, dengue virus, and yellow fever virus.
Zika virus was first identified in Uganda in 1947 in a Rhesus macaque monkey during yellow fever surveillance.
Human infections were sporadically detected across Africa and Asia from the 1960s to the 1980s.
Major outbreaks of Zika virus occurred from 2007 onwards in Africa, the Americas, Asia, and the Pacific.
In 2015, an outbreak in Brazil linked Zika virus infection to microcephaly, leading to global concern.
The World Health Organization declared a Public Health Emergency of International Concern (PHEIC) from February to November 2016 due to the association between Zika virus, microcephaly, and neurological disorders.
Global cases of Zika virus have declined since 2017, but transmission continues at low levels in several countries, particularly in the Americas.
Local mosquito-transmitted cases were reported in Europe in 2019, and an outbreak occurred in India in 2021.
A total of 89 countries and territories have reported evidence of mosquito-transmitted Zika virus infection, although global surveillance is limited.
In Africa, the virus maintains a sylvatic cycle involving nonhuman primates and mosquitoes.
In other regions, Zika virus has adapted to a human-mosquito-human transmission cycle.
Antibodies against Zika virus have been detected in various animals, including monkeys, bats, goats, rodents, and sheep.
Structure of Zika Virus
The mature Zika virus (ZIKV) resembles a golf ball with a smooth surface, where the major surface protein E lies parallel to the viral membrane.
The virus is approximately 50 nm in size, with 180 copies of E and M proteins embedded in its viral membrane.
ZIKV has a positive-stranded RNA genome encased within a lipid envelope and three structural proteins.
The E protein is composed of four domains: a stem transmembrane domain pair and three ectodomains, labeled I, II, and III.
The E protein dominates the outer surface of the virus, and about 50% of this protein is conserved between ZIKV and dengue virus (DENV) strains.
The smaller M protein is situated beneath the larger E protein, with 180 E and M proteins arranged in a raft-like configuration.
The prM glycoprotein is linked to the viral membrane, and in immature ZIKV, trimers of prM-E heterodimers form spiked projections that are organized with icosahedral symmetry. These immature virions assemble on the endoplasmic reticulum.
As the immature virions pass through the secretory pathway, the prM undergoes cleavage by a host furin-like protease.
The mature virion has a smooth surface composed of 90 E protein dimers, which are aligned parallel to the viral membrane.
Genome Structure of Zika Virus
Genome Composition:
Zika virus (ZIKV) has a positive-sense, single-stranded RNA genome.
The genome is approximately 10.7 kilobases (kb) in length.
It contains a single open reading frame (ORF) flanked by two untranslated regions (UTRs) at the 5′ and 3′ ends.
Untranslated Regions (UTRs):
The 5′ and 3′ UTRs are crucial for viral replication and translation.
Polyprotein Processing:
The ORF is translated into a single polyprotein.
This polyprotein is cleaved co- and post-translationally by:
Viral proteases (indicated by arrows in the figure).
Host proteases (indicated by diamonds in the figure).
Structural Proteins:
Capsid (C): Encapsulates the viral RNA.
pre-Membrane (prM): Involved in virus maturation.
Envelope (E): Essential for host cell entry and immune evasion.
Non-Structural Proteins:
NS1: Plays a role in immune evasion.
NS2A, NS2B: Involved in replication complex formation.
NS3: Functions as a protease and helicase.
NS4A, NS4B: Involved in altering host cell membranes for replication.
NS5: Acts as RNA-dependent RNA polymerase (RdRp) and methyltransferase, crucial for RNA synthesis and capping.
Functional Roles:
Structural proteins (C, prM, E): Form the viral particle structure.
Non-structural proteins (NS1-NS5): Facilitate genome replication, polyprotein processing, and regulation of host immune response.
Epidemiology of Zika Virus
Zika virus (ZIKV) was first isolated in Uganda in 1947 during a study of yellow fever.
Initially, ZIKV was associated with sporadic human infections in Africa and Asia.
The first significant outbreak occurred in 2007 on the coast of Central Africa and in Micronesia.
From 2013 to 2016, outbreaks were reported in French Polynesia, New Caledonia, Easter Island, Cook Islands, Samoa, and American Samoa.
ZIKV rapidly spread to South and Central America, with the first U.S. locally transmitted case detected in July 2016.
The incidence of ZIKV is likely underestimated due to limited routine laboratory testing.
ZIKV is a single-stranded RNA virus belonging to the Flavivirus genus in the Flaviviridae family.
The ZIKV genome encodes a polyprotein that is cleaved into capsid, envelope, pre-membrane, and non-structural proteins.
ZIKV produces untranslated RNA that may regulate host antiviral response and induce host cell death.
ZIKV spread to Asia in the 1960s, but significant outbreaks only occurred after 2007.
In 2007, ZIKV caused an outbreak on the Yap Islands in Micronesia, infecting 75% of the population.
A second outbreak occurred in French Polynesia in 2013-2014, with over 50% of the population infected.
ZIKV spread to other Pacific Islands and South America, first detected in northeastern Brazil in 2015.
Severe complications during these outbreaks included Guillain-Barré Syndrome and congenital ZIKV syndrome, characterized by microcephaly in newborns.
By January 2018, more than 3,700 cases of congenital ZIKV syndrome were reported in Brazil.
ZIKV is now considered part of the TORCH pathogens group, known for causing severe complications during pregnancy.
The incidence of ZIKV has decreased significantly since 2017, possibly due to high herd immunity in regions like French Polynesia and Northeast Brazil.
As of July 2019, 87 countries and territories in Africa, Asia, the Americas, and the Pacific have reported ZIKV presence.
Microcephaly cases associated with ZIKV were detected in Angola, Cabo Verde, and Guinea-Bissau, though the connection is unclear due to limited surveillance.
Despite endemic Aedes aegypti populations, 61 countries and territories have not documented autochthonous ZIKV transmission.
Autochthonous ZIKV transmission in Europe was first reported in southern France in 2019, where Aedes albopictus is the potential mosquito vector.
ZIKV has the potential to emerge or re-emerge in countries with Aedes mosquito vectors.
Surveillance and research on arboviral diseases like ZIKV should be increased due to their global threat.
Although ZIKV extensively spread in the Americas, outbreaks in Asia were smaller, with the first outbreak in Singapore in 2016.
In Africa, despite the virus's origin, large-scale outbreaks have not occurred, possibly due to undetected circulation and unknown factors.
In Africa, the first ZIKV outbreak occurred in Cabo Verde in 2015, caused by an Asian lineage strain imported from Brazil.
Other African outbreaks occurred in Angola and Gabon, with some cases of microcephaly reported.
The pathogenicity of African lineage ZIKV strains is high, but the link to microcephaly in human populations has not been proven.
ZIKV re-emerged in Asia with outbreaks in Singapore and India in 2016 and 2018, respectively, involving the "old Asian lineage."
The potential for a future epidemic in Europe exists, but Aedes albopictus, the primary European vector, may have limited transmission potential.
The first human ZIKV infections were detected in Uganda and Tanzania in 1952.
The complete genome of a ZIKV strain was sequenced in 2006 from a patient in Thailand.
The first ZIKV outbreak outside Africa or Asia occurred in 2007 on the Yap Islands, marked by rash, arthralgia, and conjunctivitis.
A larger epidemic occurred in French Polynesia in 2013-2014, with about 30,000 symptomatic infections and reports of severe complications.
Smaller outbreaks followed in 2014 in New Caledonia, Cook Islands, Easter Island, and in 2015 in Vanuatu, Solomon Islands, Samoa, and Fiji.
ZIKV emerged in the Americas in February 2015, spreading to 12 countries by the end of the year.
The potential link between maternal ZIKV infection and congenital syndrome was suggested in September 2015 after a significant increase in microcephaly cases in Brazil.
Similar clusters of microcephaly were observed retrospectively in French Polynesia during the 2013-2014 outbreak.
Studies suggested an increase in Guillain-Barré syndrome in adults with ZIKV infection.
In February 2016, WHO declared ZIKV-related microcephaly and other neurological disorders a Public Health Emergency of International Concern (PHEIC).
ZIKV is now endemic in tropical areas, with nearly half of the global population living in areas at risk of infection.
The re-emergence of ZIKV in the Americas has been linked to urbanization, changes in agricultural practices, and deforestation.
Transmission of Zika Virus
Zika virus (ZIKV) is primarily transmitted to humans through the bite of infected Aedes aegypti mosquitoes.
Other Aedes species, including Aedes albopictus, A. africanus, A. luteocephalus, A. furcifer, and A. taylori, also contribute to ZIKV transmission.
ZIKV can be transmitted through sexual contact with an infected individual, including male-to-female, female-to-male, and male-to-male transmission.
The virus can be transmitted through blood transfusions and organ transplantation, although transmission via organ transplantation has not been firmly confirmed.
ZIKV can cross the placental barrier, leading to congenital infections in fetuses, which may result in severe congenital malformations, such as Congenital Zika Syndrome (CZS).
The virus has been detected in breast milk, but transmission through breastfeeding has not been confirmed; the WHO recommends breastfeeding as the benefits outweigh potential risks.
Laboratory workers are at risk of accidental exposure to ZIKV, emphasizing the need for caution and safety protocols.
Aedes aegypti is the primary vector for ZIKV, and its distribution in tropical regions places populations at high risk for outbreaks.
Aedes albopictus can also transmit ZIKV but plays a minor role in outbreaks; it has been reported as a vector in Gabon (2007) and in sporadic cases in France.
Other Aedes species with limited geographic distributions, such as Aedes hensilli on Yap Island and Aedes polynesiensis in French Polynesia, can also transmit ZIKV.
Vertical transmission from mother to child occurs in 20% to 30% of infected pregnant women, with the first trimester posing the highest risk for CZS.
Sexual transmission of ZIKV was first suspected in 2008 when a traveler infected his partner after returning from an endemic area.
ZIKV RNA can persist in semen for several months, but the presence of RNA does not necessarily indicate infectious virus; male fertility may be impacted by ZIKV, potentially leading to decreased sperm count and motility.
ZIKV transmission through blood transfusion is a potential risk, and strategies like testing blood donations for ZIKV RNA or deferring donations from individuals who have traveled to endemic areas have been implemented.
Although ZIKV has been detected in urine and saliva, transmission through contact with these body fluids has not been confirmed; one suspected case of interhuman transmission via body fluids has been reported, but it remains unproven.
Replication of Zika Virus
Attachment/Adsorption:
The Zika virus attaches to host cells through its envelope E proteins, which interact with host receptors such as C-type lectin receptors (CLRs).
These receptors are commonly expressed on myeloid cells, including monocytes, macrophages, and dendritic cells.
Penetration:
The virus enters the host cell via clathrin-mediated endocytosis, a process aided by molecular mimicry.
The viral particle is engulfed in a clathrin-coated vesicle.
Uncoating:
The clathrin-coated vesicle is transported away from the plasma membrane, and the clathrin coat is removed.
The endocytic vesicle is then delivered to early endosomes, which mature into late endosomes.
As the endosome matures, the pH changes, causing the viral membrane to fuse with the endosomal membrane.
This fusion releases the viral RNA genome into the cytoplasm.
Biosynthesis:
The positive-stranded ssRNA genome is translated into a single polyprotein.
This polyprotein is cleaved into structural and non-structural proteins necessary for viral replication.
Viral replication occurs on the surface of the endoplasmic reticulum (ER).
A double-stranded RNA (dsRNA) genome is synthesized from the positive-stranded ssRNA.
The dsRNA serves as a template for the production of viral mRNA and new ssRNA genomes through transcription and replication.
Assembly:
Viral assembly takes place at the endoplasmic reticulum, where new viral particles are formed.
The assembled virions then bud off from the ER and are transported to the Golgi apparatus.
Maturation:
Viral maturation occurs in the Golgi apparatus.
During this process, the prM protein of the immature virion is cleaved, resulting in a mature viral particle.
The mature virion is then prepared for release.
Release:
The mature viral particle is released from the host cell through the process of exocytosis.
The virus is then free to infect new cells, continuing the cycle of infection.
Pathogenesis of Zika Virus
Target Cells:Zika virus (ZIKV) infects human dermal fibroblasts, epidermal keratinocytes, immature dendritic cells, monocytes, and macrophages.
Entry Factors: DC-SIGN, Tyro3, AXL, and TIM-1 facilitate viral entry into these cells.
Replication and Immune Response: ZIKV replication triggers Type I interferon production in infected cells and activates an antiviral immune response.
Virus Spread: After initial infection in the skin, ZIKV spreads to lymph nodes, replicates, and causes primary viremia. It then disseminates to visceral organs through the bloodstream.
Detection and Viremia: ZIKV RNA is detectable in blood within 10 days of infection, with higher viral loads during prolonged viremia.
Viral Shedding: High levels of viral shedding occur in urine, saliva, semen, tears, and cervical mucus. The virus can remain in semen for months after clearance from blood.
Immune Response: Both humoral and cell-mediated immune responses are triggered by ZIKV infection. IgM antibodies are usually detectable for 2-3 months, while IgG antibodies can persist for months or years, providing long-term immunity.
Clinical Manifestations of Zika Virus
Asymptomatic or Mild Symptoms: Zika virus infection can be asymptomatic. When symptoms occur, they typically appear 3-14 days after infection and last for 2-7 days. Common symptoms include:
Zika virus can be cultured by inoculating chicken embryo yolk sacs, allantoic sacs, and chorioallantoic membrane.
It can also be cultured in cell lines such as Vero, rhesus monkey kidney, and pig kidney cells.
Suckling mice can be used for inoculation, though they are less sensitive compared to cell cultures.
The virus has been successfully cultured from human blood, semen, and urine.
Molecular Detection of ZIKV RNA:
Detection involves a two-step gene amplification procedure:
Reverse transcription of genomic RNA into complementary DNA (cDNA).
Conversion of cDNA to double-stranded DNA, followed by amplification.
Real-time PCR is preferred for faster detection compared to conventional PCR.
Serological Diagnosis:
ELISA is used to detect ZIKV antibodies.
Confirmatory testing is performed using the Plaque Reduction Neutralization Test (PRNT), which is the “gold standard” for differentiating anti-Flavivirus antibodies.
IgM antibodies are specific to ZIKV during primary Flavivirus infections, with limited cross-reactivity with other flaviviruses.
During secondary Flavivirus infections, there is significant cross-reactivity, observed in both IgM ELISA and PRNT90.
PRNT is costly and usually conducted in specialized laboratories.
Diagnosis in Endemic Countries:
In regions with limited access to advanced molecular tests, serological testing using IgM ELISA or rapid tests is common.
Combining NS1 antigen and IgM antibody tests enhances the sensitivity and specificity of dengue fever diagnosis.
If multiple patients test negative for DENV NS1, Zika and other Flavivirus infections should be considered.
Treatment of Zika Virus
No Specific Antiviral Treatment
There are no specific antiviral drugs available for treating Zika virus infection. Management primarily focuses on alleviating symptoms and providing supportive care.
Symptomatic Relief:
Acetaminophen is recommended for relieving fever and pain associated with Zika virus infection.
Antihistamines can be used to help manage rash symptoms.
Supportive Care:
Patients are advised to drink plenty of fluids and consume a nutritious diet to aid in recovery and maintain overall health.
Avoid Certain Medications:
It is important to avoid acetylsalicylic acid (aspirin) and nonsteroidal anti-inflammatory drugs (NSAIDs) due to their potential to increase the risk of hemorrhagic syndrome, especially when co-infection with other flaviviruses is a concern.
Patient Isolation:
During the viremic phase of infection, isolation of the patient is recommended to minimize the risk of virus transmission through mosquito bites to other individuals.
Prevention and Control of Zika Virus
Vaccination Status:
As of now, there is no available vaccine for Zika fever, although several vaccines are in development.
Preventive Measures:
Mosquito Control: Eliminate mosquito breeding grounds through environmental modifications and the use of insecticides. This includes removing standing water and maintaining clean surroundings.
Personal Protection: Use mosquito repellents, coils, vaporizers, and oils to prevent mosquito bites. Wearing long-sleeved clothing and long pants can also help reduce skin exposure.
Minimize Exposure: Avoiding exposure in areas where Zika virus remains endemic is crucial to reduce the risk of infection.
Laboratory Development:
Countries at high risk for Zika virus infection should establish basic virologic and serologic laboratories. These facilities are essential for accurate diagnosis and effective management of Zika virus cases.
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