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The Zika virus (ZIKV) is a mosquito-borne virus in the member of the Flaviviridae family, genus Flavivirus. The virus was first found in 1947 in the blood of a monkey in Uganda’s Zika Forest giving the virus its name. There are two lineages of the Zika virus, African and Asia. The Asian strain caused outbreaks in Micronesia in 20019 and French Polynesia in 2013-2014. (White, Wollebo, David Beckham, Tyler, & Khalili, 2016) Zika was transmitted originally in a sylvatic cycle between monkeys and Aedes mosquitos in Africa but it was spread by the reciprocal infection of man and mosquitos. It can also be spread by sexual transmission or by blood transfusions. (White et al., 2016) The first direct evidence of the presence ZIKV in the Asian continent and the first proof of its transmission by an urban vector as found through the isolation of the virus from A. aegypto mosquitos in Malaysia in 1966. It wasn’t until 2015 that the virus really got national attention due to the increased number of microcephaly in neo-natal cases in Latin America. ((Basak et al., 2019) Some of the symptoms of ZIKV include a rash, itching all over the body, headache, joint pain with possible swelling, muscle pain, red eyes, lower back pain and pain behind the eyes. Even though ZIKV itself can be dangerous, the association that the virus has with microcephaly in pregnant women and Guillain-Barre syndrome makes research more urgent than ever.
ZIKV has a genome about 11 kb in length, made up of single stranded, positive sense, RNA that encodes 3 structural and 7 nonstructural proteins expressed as single polyprotein undergoing cleavage. The virions are enveloped and icosahedral. The genome of the Zika virus replicates in the cytoplasm of infected host cells. Zika includes several parts, including the capsid protein about 13 kDa in length, a lipid bilayer containing protein M and envelope protein E. The genomic RNA lacks a poly-A tail at the 3’ end. (White et al., 2016) The prM and envelope E protein mediate the virion attachment to and fusion with host-cell membranes. The NS proteins (non-structural proteins) have many roles that include promoting replication and sometimes even evading the host innate immune response. When infected, the virus induces perinuclear membrane arrangements to create an environment for replication called replication factories. Some of the changes that happen are the appearance of convoluted membranes, formation of vesicles that have been invaginated (clustered double-membrane vesicle packets) and even cellular cytoskeleton changes. It replicates via intermediary synthesis of negative-sense antigenomes. ZIKV is has been found to infect multiple cells types in the brain such as glial cells, neurons, and neuronal stem cells. (Liu et al., 2018) The genome contains so many crucial portions for the virus to replicate and infect but the way that it does this can be complex. (Basak et al., 2019)
Flavivirus bind to surface of target cells by interactions with viral surface glycoproteins and cellular cell surface receptors. The virions undergo receptor-mediated endocytosis and are internalized into clathrin-coated pits. (White et al., 2016) Steps of replication happen through the production of double-stranded RNA intermediates. Once assembled in the ER, progeny virus particles form a multivescular body-like structure and exit into the cytoplasm through a channel most likely through abscission from [membrane or a pore on the multivesicular body. Particle budding also is observed in other areas of the ER and away from Vp suggesting mature virions are trafficked through a secretory pathway for release from cell. (Liu et al., 2018) ZIKV uses the host cytoplasmic membrane for replication of its genome and the host attempts to control the infection with several responses such as interferon release, unfolded protein/ER response, autophagy and apoptosis. The translation of the viral proteins from the RNA happens from the long open reading frame to make a large polyprotein that is cleaved co- and post-translationally into the viral proteins and leads to replication. This replication starts with the synthesis of negative-strand RNA (template) for synthesis of copies of the positive-strand RNA. This requires several viral NS proteins. (White et al., 2016) One of the least known things about Zika is the mechanism at which flavivirus migrate to the CNS. There are three possible migration pathways currently being tested: through peripheral nerves and after mosquito bite involving retrograde transportation through axons, through the blood-brain barrier with altered permeability resulting from presence of pro-inflammatory species, and carried by immune cells known as “Trojan horse”. (de Oliveira et al., 2019). From the initial stage in Uganda, the ZIKV has many alterations. There are two major groups: one with older sequences from the African continent and another with more recent Asian, Pacific, and American sequences. (Basak et al., 2019) The way the ZIKV attaches, replicates and exits has many different parts to it and one of the most interesting is how ZIKV interacts with the immune system. (White et al., 2016)
ZIKV can evade the immune system by regulating the type I interferon response with its encoded NS5 protein. Compared to other flaviviruses, ZIKV sexual transmission makes it unique and gives the potential for human-to-human transmission. The most common is male to female which suggests a difference between the sexes. In females, a strong response inhibits the virus to control the infection. In males, however, the response correlates with viral persistence. (Arévalo Romero et al., 2019) One approach to study the pathogenesis has been to infect neonatal mice since adult wild-type immunocompetent mice are resistant to ZIKV infection. Infected neonatal wild-type mice showed infiltration of T cells into the central nervous system, very similar to models of neuro-invasive flavivirus infection. Mouse models have also shown that the virus can accumulate in the blood, spleen, brain, spinal cord, kidney, and eye. Studies in pregnant female mice have shown that ZIKV infects trophoblasts and fetal endothelial cells of the placenta and then crosses the placenta to infect the fetal head. It is also important to note that another study also found that ZIKV RNA persisted in saliva and seminal fluids for at least 3 weeks after the virus was not found in peripheral blood. Animal and human studies of ZIKV pathogenesis have also shown broad tissue and cell tropism for ZIKV as well as the ability to cause severe organ disease and placental and congenital infection. (Miner & Diamond, 2017) It’s important to note that these mechanisms are vital to production of vaccines.
As of now there are no vaccines available for Zika but there are several vaccines in development. It is reported that there are about 14 vaccines currently under development at Clinical Phase Trial I and 2 vaccines have moved to Clinical Phase Trial II. They are either DNA-based vaccines or inactivated whole Zika Virus vaccines. There are also two recombinant viral vectors, a peptide vaccine based on mosquito salivary proteins and another that utilizes prM-E mRNA transcript of ZIKV. One of the biggest challenges in administering Zika vaccines is the naturally phenomenon called antibody dependent enhancement or ADE. This phenomenon is reported in cases of secondary Dengue fever because of Zika’s close relation to Dengue, someone with a Zika vaccination might be severely affected by ADE if they are naturally or otherwise infected with ZIKV. (Basak et al., 2019) Currently in the Garg and Joshi lab they have developed virus-like particles that act as reporter genes with fluorescent tag so that the actual live virus doesn’t have to be tested. The lab has been the first to generate a stable cell line that secretes Zika CprME VLP (virus-like particles) by natural NS2B-3 cleavage which show incorporation of capsid in CprME VLPs and complete protection. This is a huge breakthrough for the vaccine platform and is safe for use in pregnant women. (Garg, Mehmetoglu-Gurbuz, Ruddy, & Joshi, 2019) There are also several carbohydrate compounds being tested to see if they can lower the infectivity of ZIKV as well as timepoint experiments being used to see if those compounds have the capability of lowering infectivity even after exposure to the virus. Several compounds have already shown promising results and will be further tested for the rest of the year. Another new approach is the use of peptide vaccines. Epitopes from conserved regions among proteins with high solvent accessibility are selected for the antiviral vaccine. These epitopes are then tested for population HLA sensitivity and autoimmune risks. At the end rank-based epitopes are chosen to more analysis such as efficacy, longevity, range, side effects, etc. There have been many articles pointing to suitable and effective epitopes found in the capsid, envelope, NS2A, NS3, NS4B, and NS5 proteins of the virus. (Basak et al., 2019) There are a few drug targets that have the potential to make an impact on the fight against ZIKV.
As discussed previously, viral glycoproteins play an important role for virus infection and replication therefore envelope glycoprotein inhibitors are well researched for anti-ZIKV activity. There are a few inhibitors that have also had promising results. Some of these include protease inhibitors, NS3 helicase inhibitors (bind to RNA and ATP binding sites), NS4B inhibitors (even though this research faces many challenges because of poor ADME properties of the inhibitors), NS5 methyltransferase inhibitors (Sinefungin is one such example), NS5 polymerase inhibitors, and non-nucleoside RNA polymerase inhibitors. (Basak et al., 2019) The virus itself can be lethal but other complications can arise from being infected.
One of the most unique aspects of ZIKV is the association that it has with microcephaly in pregnant women and Guillain-Barre syndrome (GBS). GBS is a potentially life-threatening peripheral nerve disease characterized by a very fast onset of bilateral weakness that progresses to paralysis. It could also be accompanied by sensory symptoms. It occurs about 1-3 weeks after ZIKV infection and is believed to trigger a pathogen-specific immune response that interacts with peripheral nervous system antigens. (Dhiman, Abraham, & Griffin, 2019) Typically GBS is a rare neurological disorder and the exact cause (when not infected with ZIKV) is unknown. Currently there is no known cure for GBS but some therapies can help to lessen the seriousness and shorten the recovery time. (NIAMS, 2016) Microcephaly is a condition where the circumference of the head is smaller than normal because the brain stops developing properly or has stop growing completely. There is no treatment for microcephaly but there are ways to lower the impact of the deformities and neurological handicaps. There are early childhood programs such as physical, speech and occupational therapies for therapists to increase abilities and minimize problems. (NIAMS, 2016) Neuroinflammation has been proposed as one of the key factors that contribute to ZIKV-related microcephaly especially those that are mediated by glial cells. (de Oliveira et al., 2019) Pregnant women should be questioned about potential exposure before and during pregnancy so that tests can be done. Placental testing can be used if diagnosis is unclear. Serial ultrasounds are performed to look for congenital infection and then every 4 weeks. (Leeper & Lutzkanin, 2018) Someone who could have been infected has to take precautions and inform doctors so that they can be prepared and have the possibility to lessen or manage symptoms.
While treatment and vaccines haven’t yet been yet completed or approved, the emergence of such a unique virus has pushed the science community to find either a vaccine or a treatment for this virus. While the virus had been around for a number of years this association that was finally made with microcephaly and GBS gave the science community a push into finding a way to combat it. With the numbers in Latin America swiftly rising and the virus reaching more places than ever before, we have to use all our resources. The uniqueness of ZIKV not only in structure but the type of cells that are affected can lead to not only death but also pregnancy abnormalities or negative effects on the nervous system. In the coming years as technology advances and as we continue to do research, we are very close to finding a treatment or a vaccine that could help us eliminate this potentially devastating virus.
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