Zika Virus (ZIKV)- An Overview

Zika virus (ZIKV) is a member of the flavivirus family, which includes other viruses that cause human diseases such as dengue, yellow fever, and West Nile fever. ZIKV was first isolated from a monkey in Uganda in 1947 and has since been associated with sporadic outbreaks in Africa, Asia, and the Pacific islands. In 2015-2016, ZIKV caused a large epidemic in the Americas, where it was linked to congenital malformations and neurological complications.

ZIKV, like other flaviviruses, has a spherical shape with a diameter of about 50 nm. It consists of four main components: a lipid envelope, an envelope (E) protein, a membrane (M) protein, and a single-stranded positive-sense RNA genome.

The lipid envelope is derived from the host cell membrane and contains embedded E and M proteins. The E protein is the major surface protein that mediates viral attachment, entry, and fusion with host cells. It also elicits neutralizing antibodies and cellular immune responses in the host. The E protein has four domains: a stem transmembrane domain that anchors it to the viral membrane, and three ectodomains (I, II, and III) that form the outer surface of the virus. Domain III is involved in receptor binding, while domains I and II are involved in conformational changes during fusion. The M protein is a smaller protein that lies under the E protein and stabilizes the viral envelope. It is initially synthesized as a precursor protein (prM) that prevents premature fusion of E proteins in the endoplasmic reticulum. The prM protein is cleaved by a host protease during viral maturation in the Golgi apparatus.

The RNA genome of ZIKV is about 10.7 kb long and encodes a single polyprotein that is cleaved by viral and host proteases into three structural proteins (C, prM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The structural proteins form the viral particle, while the non-structural proteins are involved in viral replication, polyprotein processing, and modulation of host immune responses. The RNA genome also has two untranslated regions (UTRs) at the 5` and 3` ends that contain regulatory elements for viral transcription, translation, and replication.

The structure and genome of ZIKV are similar to those of other flaviviruses, but there are also some differences that may affect its pathogenicity and immunogenicity. For instance, ZIKV has unique amino acid substitutions in its E protein that may alter its receptor binding specificity and antigenicity. ZIKV also has a shorter 3` UTR than other flaviviruses that may affect its RNA stability and interaction with host factors. These features may contribute to the unique epidemiology and clinical manifestations of ZIKV infection.

Zika virus (ZIKV) is a mosquito-borne flavivirus that was first isolated in Uganda in 1947 from a rhesus monkey . Since then, sporadic human infections have been reported in Africa and Asia, mostly associated with mild or asymptomatic febrile illness . The first major outbreak of ZIKV occurred in 2007 on Yap Island, Federated States of Micronesia, where about 73% of the population was estimated to be infected . Another outbreak was detected in 2013-2014 in French Polynesia and other Pacific islands, such as New Caledonia, Cook Islands, and Easter Island . These outbreaks were also characterized by mild symptoms, but some cases of neurological complications, such as Guillain-Barré syndrome and congenital malformations, such as microcephaly, were reported .

The ZIKV epidemic reached the Americas in 2015, when Brazil confirmed its first autochthonous transmission . The virus then rapidly spread to other countries and territories in South and Central America, the Caribbean, and North America, reaching a peak of reported cases in 2016 . According to the Pan American Health Organization (PAHO), more than 750,000 suspected and confirmed cases of ZIKV infection have been reported in the Americas as of February 2022 . The ZIKV epidemic in the Americas also revealed a strong association between ZIKV infection during pregnancy and congenital Zika syndrome (CZS), a spectrum of birth defects that includes microcephaly, brain abnormalities, eye defects, hearing loss, and impaired growth . The World Health Organization (WHO) estimated that the risk of CZS ranged from 1% to 13% among pregnant women infected with ZIKV in the first trimester .

ZIKV transmission continues to occur in several countries at low levels, but with potential for re-emergence . As of April 2021, WHO reported 84 countries or territories with current or previous evidence of ZIKV transmission . Two new countries, Angola and Ethiopia, were added to the list based on peer-reviewed published data . In Southeast Asia, where ZIKV is endemic but often underdiagnosed, several outbreaks have been detected since 2016, including a large outbreak in Singapore that affected more than 400 people . The first cases of CZS linked to ZIKV infection in Southeast Asia were also reported in Thailand and Vietnam in 2016-2017 .

The global epidemiology of ZIKV infection is dynamic and complex, influenced by multiple factors such as viral evolution, vector ecology, human behavior, environmental changes, surveillance capacity, and diagnostic tools. The emergence of ZIKV as a public health threat highlights the need for sustained vigilance and preparedness to detect and respond to future outbreaks, as well as to monitor the long-term consequences of ZIKV infection on human health. Moreover, the development of effective vaccines and therapeutics against ZIKV remains a priority for preventing and controlling this disease.

Zika virus is mainly transmitted by the bite of an infected Aedes species mosquito, especially Ae. aegypti and Ae. albopictus . These are the same mosquitoes that spread dengue and chikungunya viruses. They typically lay eggs in or near standing water in containers like buckets, bowls, animal dishes, flower pots, and vases. They prefer to bite people, and live indoors and outdoors near people. They bite during the day and night.

A mosquito becomes infected with Zika virus when it bites an infected person during the period of time when the virus can be found in the person’s blood, usually only through the first week of infection. Infected mosquitoes can then spread the virus to other people through bites.

Zika virus can also be transmitted from a pregnant woman to her fetus during pregnancy or around the time of birth. Zika virus infection during pregnancy can cause infants to be born with microcephaly and other congenital malformations as well as preterm birth and miscarriage.

Zika virus can also be transmitted through sexual intercourse with an infected partner. Zika virus can be passed through sex, even if the infected person does not have symptoms at the time. It can be passed before, during, or after symptoms appear. The virus may also be passed by a person who carries the virus but never develops symptoms. Zika virus can remain in semen longer than in other body fluids, such as vaginal fluids, urine, and blood.

Zika virus can also be transmitted through blood transfusion and organ transplantation from an infected donor. There have been multiple reports of possible blood transfusion transmission cases in Brazil. Zika virus has also been found in breast milk, but it is not clear if it can be transmitted through breastfeeding .

Once Zika virus particles are in the human body, they must enter individual cells in order to replicate and make more viruses. Cell entry is possible because a Zika virus particle carries specific proteins on its outer envelope that interact with receptor proteins on human cells. The receptors that Zika virus uses are not fully known, but some candidates include C-type lectin receptors (CLRs), AXL, Tyro3, and TIM-1. These receptors are expressed on various cell types, such as skin cells, immune cells, and neural cells.

After binding to a receptor, the virus particle is taken up by the cell through a process called endocytosis. This means that the cell membrane forms a pocket around the virus and pinches off to form a vesicle inside the cell. The vesicle then fuses with another membrane-bound compartment called an endosome, where the pH is lower than in the cytoplasm. The acidic environment triggers a conformational change in the viral envelope proteins, causing them to fuse with the endosomal membrane and release the viral RNA genome into the cytoplasm.

The viral RNA genome is a single-stranded molecule that contains all the genetic information for making new virus particles. It has two main functions: it serves as a template for making more RNA copies, and it serves as a messenger for making viral proteins. The viral RNA is translated by the cell`s ribosomes into a long polyprotein that is then cleaved by viral and cellular proteases into individual proteins. These proteins include three structural proteins (capsid, pre-membrane, and envelope) that form the structure of the virus particle, and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) that are involved in RNA replication and modulation of host immune response.

The viral RNA replication takes place at the surface of the endoplasmic reticulum (ER), a network of membranes that is involved in protein synthesis and transport. The viral non-structural proteins insert themselves into the ER membrane and reshape it into small spherical structures called replication complexes. These structures provide a protected environment for the synthesis of new RNA molecules from the viral template. The viral RNA polymerase (NS5) catalyzes the formation of a complementary negative-strand RNA from the positive-strand RNA template. The negative-strand RNA then serves as a template for making multiple positive-strand RNA copies that will be packaged into new virus particles.

The viral assembly occurs at the ER membrane as well. The capsid protein binds to the positive-strand RNA and forms a nucleocapsid core. The nucleocapsid then buds into the ER lumen and acquires a membrane envelope containing the pre-membrane and envelope proteins. These immature virus particles then travel through the secretory pathway of the cell, passing through the Golgi apparatus where they undergo further maturation. The pre-membrane protein is cleaved by a cellular enzyme called furin into membrane and pr peptides. The pr peptide is released from the virus particle, allowing the envelope proteins to rearrange into dimers that give the virus its characteristic smooth surface.

The mature virus particles are then released from the cell by exocytosis, a process that involves fusion of vesicles containing the virus with the cell membrane. The released virus particles can then infect new cells or be transmitted to other hosts through mosquito bites or other routes.

The pathogenesis of Zika virus (ZIKV) is not fully understood, but some studies have suggested possible mechanisms and factors that influence the viral infection and its outcomes. The human dermal fibroblasts, epidermal keratinocytes, immature dendritic cells, monocytes, macrophages, and neural progenitor cells are among the cell types that can be infected by ZIKV. The virus enters the cells through various receptors, such as AXL, TYRO3, TIM-1, and DC-SIGN. The viral replication occurs in the cytoplasm, but ZIKV antigens have also been detected in the nuclei of infected cells.

After the initial infection at the skin or mucosal site, ZIKV spreads to the lymph nodes and the bloodstream, causing primary viremia. The virus can then infect various tissues and organs, such as the placenta, the brain, the eye, the testis, and the salivary glands. The viral load and persistence in different body fluids may vary depending on the host immune response and other factors. ZIKV can cross the placental barrier and infect the fetal tissues, especially the developing brain, leading to congenital malformations such as microcephaly. ZIKV can also trigger an inflammatory response and disrupt the blood-brain barrier, resulting in neurological complications such as Guillain-Barré syndrome, myelitis, and encephalitis.

The host immune response to ZIKV infection involves both innate and adaptive immunity. ZIKV infection induces the production of type I interferons (IFNs) and pro-inflammatory cytokines that limit viral replication and activate antiviral effector cells. However, ZIKV can also evade or modulate the host immune response by several mechanisms, such as suppressing IFN signaling, inhibiting antigen presentation, inducing apoptosis of immune cells, and generating defective viral particles that act as decoys. Moreover, ZIKV infection can induce cross-reactive antibodies with other flaviviruses that may enhance or impair viral clearance and pathogenesis.

Understanding the pathogenesis of ZIKV is essential for developing effective strategies for prevention and treatment of ZIKV infection and its associated diseases.

Zika virus infection may be asymptomatic in up to 80% of the cases . Among those who do develop symptoms, they typically start 3–14 days after infection, are generally mild and last for 2–7 days . The characteristic clinical findings are:

• Acute onset of fever
• Maculopapular rash
• Arthralgia (involving the small joints of the hands and feet)
• Conjunctivitis
• Muscle pain
• Headache
• Pain behind the eye
• Vomiting

Other symptoms and complications that have been reported include:

• Myalgia
• Asthenia
• Peripheral edema
• Gastrointestinal disturbances (abdominal pain, nausea, diarrhea)
• Congenital microcephaly and other congenital malformations in infants born to women infected during pregnancy
• Guillain-Barré syndrome, neuropathy and myelitis in adults and children
• Fetal losses in women infected during pregnancy
• Acute myelitis
• Meningoencephalitis
• Axillary and/or inguinal lymphadenopathy
• Leukopenia with monocytosis
• Thrombocytopenia

Clinical illness is usually mild and does not require hospitalization. However, severe disease and case fatality have been observed in some outbreaks. Zika virus infection during pregnancy can cause serious birth defects and adverse pregnancy outcomes, such as microcephaly, brain abnormalities, eye defects, hearing loss, and impaired growth. Zika virus infection is also associated with neurological disorders, such as Guillain-Barré syndrome, which is a rare condition that causes muscle weakness and paralysis.

Zika virus infection should be suspected in patients with compatible clinical features who have traveled to or reside in areas with ongoing Zika virus transmission. The differential diagnosis for Zika virus infection is broad and includes other mosquito-borne diseases, such as dengue, chikungunya, malaria, and yellow fever, as well as other viral infections, such as leptospirosis, rickettsia, rubella, measles, parvovirus, enterovirus, adenovirus, and alphavirus infections. Laboratory diagnosis is based on the detection of virus, viral nucleic acid, or virus-specific antibodies in blood or other body fluids.

There is no specific antiviral treatment for Zika virus infection. Treatment is supportive and includes rest, fluids, analgesics, antipyretics, and antihistamines. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided due to the risk of hemorrhagic syndrome with other flaviviruses. Prevention and control measures include avoiding mosquito bites, using insect repellents and nets, wearing protective clothing, eliminating mosquito breeding sites, practicing safe sex or abstinence, and seeking prenatal care if pregnant. No vaccine is currently available for Zika virus infection.

To diagnose Zika virus infection, a doctor or other healthcare provider will ask about any recent travel and any signs and symptoms of the disease. They may order blood or urine tests to help determine if the patient has Zika virus. There are two main types of tests for Zika virus infection: molecular tests and serological tests.

Molecular tests

Molecular tests look for the presence of the Zika virus RNA in the body fluids of the patient. These tests are also known as nucleic acid amplification tests (NAATs) or polymerase chain reaction (PCR) tests. Molecular tests are more accurate and reliable than serological tests, especially during the acute phase of infection and up to 14 days after the onset of symptoms. Molecular tests can also distinguish Zika virus from other flaviviruses, such as dengue, yellow fever, or West Nile virus. However, molecular tests require specialized equipment and trained personnel, and may not be widely available in some areas.

Serological tests

Serological tests look for the antibodies that the body produces to fight Zika virus infection. These tests are also known as enzyme-linked immunosorbent assays (ELISAs) or rapid diagnostic tests (RDTs). Serological tests are less sensitive and specific than molecular tests, and may not detect Zika virus infection in the early stages of the disease. Serological tests may also cross-react with antibodies against other flaviviruses, making it difficult to confirm Zika virus infection in areas where there may have been possible co-infection or prior infection with dengue or other related viruses. Serological tests are simpler and cheaper than molecular tests, and can be performed in point-of-care settings.

Depending on the symptoms, travel history, and exposure risk of the patient, a doctor or other healthcare provider may order one or both types of tests for Zika virus infection. Testing should take place as soon as possible after the onset of symptoms, while the virus is still detectable in the body. Testing is recommended for:

• People who have symptoms of Zika virus infection and have traveled to an area with a current or recent Zika virus outbreak
• Pregnant women who have symptoms of Zika virus infection and have traveled to an area with risk of Zika virus transmission
• Pregnant women who have no symptoms of Zika virus infection but have traveled to an area with risk of Zika virus transmission
• Pregnant women who have had ultrasound findings or delivered a baby with birth defects that may be related to Zika virus infection
• People who have had sexual contact with a person who has confirmed or suspected Zika virus infection
• People who have received blood transfusions or organ transplants from donors who have traveled to an area with risk of Zika virus transmission

Testing is no longer routinely recommended for people who have no symptoms of Zika virus infection and have not traveled to an area with risk of Zika virus transmission.

There is no specific antiviral treatment or vaccine for Zika virus infection. The infection is usually mild and self-limiting, and only supportive care is available. The following are some of the treatment options for Zika virus infection:

• Get plenty of rest and drink fluids to prevent dehydration.
• Take medicine such as acetaminophen (Tylenol®) to reduce fever and pain. Do not take aspirin and other non-steroidal anti-inflammatory drugs (NSAIDS) until dengue can be ruled out to reduce the risk of bleeding .
• If you are taking medicine for another medical condition, talk to your healthcare provider before taking additional medication.
• If you are pregnant, consult your healthcare provider for regular prenatal care and monitoring of fetal development.
• If you think you may have or had Zika, tell your doctor or healthcare provider and take steps to protect others from getting infected.
• If you are caring for a person with Zika, take precautions to avoid exposure to the person’s blood and body fluids (urine, stool, vomit) by wearing gloves, washing hands, and cleaning surfaces with disinfectants.
• During the viremic phase of the infection, isolate the patient to prevent transmission of the virus through mosquito bites to other people.

Zika virus infection can have serious consequences for pregnant women and their fetuses, as well as for people with certain neurological conditions. Therefore, it is important to prevent and control the spread of the virus and its complications. The main prevention and control measures for Zika virus are:

• Avoiding mosquito bites: Zika virus is transmitted primarily by the bite of an infected Aedes species mosquito, which are active during the day and night. To prevent mosquito bites, people should use insect repellents that contain DEET, picaridin, IR3535, oil of lemon eucalyptus, para-menthane-diol, or 2-undecanone, following the product label instructions. They should also wear long-sleeved shirts and long pants, treat clothing and gear with permethrin or buy permethrin-treated items, and use screens or air conditioning to keep mosquitoes outside .

• Reducing mosquito breeding sites: Aedes mosquitoes breed in small containers of water, such as buckets, tires, flower pots, and vases. To reduce mosquito populations, people should empty and clean these containers regularly, cover them with lids or screens, or dispose of them properly .

• Protecting sexual partners: Zika virus can be passed through sex from a person who has Zika to his or her sex partners, even if the person does not have symptoms or knows they are infected. To prevent sexual transmission of Zika, people should use condoms correctly and consistently every time they have sex (vaginal, anal, or oral), or abstain from sex during the entire pregnancy if their partner is pregnant or lives in or has traveled to an area with risk of Zika .

• Seeking medical care: People who develop symptoms of Zika virus infection, such as fever, rash, joint pain, red eyes, muscle pain, headache, pain behind the eyes, or vomiting, should seek medical care and inform their health care provider about their travel history or possible exposure to Zika. They should also avoid further mosquito bites to prevent spreading the virus to other mosquitoes .

• Testing for Zika virus infection: There are different tests available to diagnose Zika virus infection, such as molecular tests that detect the viral RNA in blood or urine samples, or serological tests that detect antibodies against the virus in blood samples. Depending on the type of test, the timing of exposure, and the presence of symptoms, the test results may vary in accuracy and interpretation. Therefore, testing for Zika virus infection should be done under the guidance of a health care provider .

• Monitoring fetal development: Pregnant women who have been exposed to Zika virus or have symptoms of Zika virus infection should have regular ultrasounds to check for fetal abnormalities, such as microcephaly (abnormally small head) or other brain defects. They should also consult with their health care provider about the risks and benefits of amniocentesis (a procedure that collects a sample of amniotic fluid from the womb) to test for Zika virus in the fetus .

• Supporting affected individuals and families: People who have been diagnosed with Zika virus infection or have complications from it, such as Guillain-Barré syndrome (a rare disorder that causes muscle weakness and paralysis) or congenital Zika syndrome (a range of birth defects caused by Zika virus infection during pregnancy), may need medical treatment and rehabilitation services to manage their condition. They may also need psychological and social support to cope with the emotional and financial challenges they face. Health care providers and community partners should provide appropriate care and assistance to these individuals and families .

• Developing vaccines and treatments: Currently, there is no vaccine or specific antiviral treatment for Zika virus infection. However, several vaccine candidates are in various stages of development and testing. Some of them are based on live attenuated viruses (weakened forms of the virus that cannot cause disease), others on recombinant proteins (synthetic versions of viral proteins that stimulate an immune response), and others on nucleic acids (genetic material that instructs cells to produce viral proteins). The development of safe and effective vaccines and treatments for Zika virus infection is a priority for public health research .

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