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4 pages, 183 KiB

Open AccessEditorial

New Advances on Zika Virus Research

by Luis Martinez-Sobrido and Fernando Almazán

Viruses 2019, 11(3), 258; https://doi.org/10.3390/v11030258 - 14 Mar 2019

Cited by 4 | Viewed by 3639

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne member of the Flaviviridae family that has historically been known to cause sporadic outbreaks, associated with a mild febrile illness, in Africa and Southeast Asia [...] Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

Research

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11 pages, 438 KiB

Open AccessArticle

The Application and Interpretation of IgG Avidity and IgA ELISA Tests to Characterize Zika Virus Infections

by Fátima Amaro, María P. Sánchez-Seco, Ana Vázquez, Maria J. Alves, Líbia Zé-Zé, Maria T. Luz, Teodora Minguito, Jesús De La Fuente and Fernando De Ory

Viruses 2019, 11(2), 179; https://doi.org/10.3390/v11020179 - 20 Feb 2019

Cited by 16 | Viewed by 4192

Abstract

In the absence of viremia, the diagnostics of Zika virus (ZIKV) infections must rely on serological techniques. In order to improve the serological diagnosis of ZIKV, ZIKV-IgA and ZIKV-IgG avidity assays were evaluated. Forty patients returning from ZIKV endemic areas, with confirmed or [...] Read more.

In the absence of viremia, the diagnostics of Zika virus (ZIKV) infections must rely on serological techniques. In order to improve the serological diagnosis of ZIKV, ZIKV-IgA and ZIKV-IgG avidity assays were evaluated. Forty patients returning from ZIKV endemic areas, with confirmed or suspected ZIKV infections were studied. Samples were classified as early acute, acute and late acute according to the number of days post illness onset. Low avidity IgG was only detected at acute and late acute stages and IgA mostly at the early acute and acute stages. The date of sampling provides useful information and can help to choose the best technique to use at a determined moment in time and to interpret low avidity IgG and IgA results, improving the serological diagnosis of ZIKV. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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22 pages, 3157 KiB

Open AccessArticle

Integrated MicroRNA and mRNA Profiling in Zika Virus-Infected Neurons

by Francine Azouz, Komal Arora, Keeton Krause, Vivek R. Nerurkar and Mukesh Kumar

Viruses 2019, 11(2), 162; https://doi.org/10.3390/v11020162 - 16 Feb 2019

Cited by 42 | Viewed by 5661

Abstract

Zika virus (ZIKV) infections have caused a wide spectrum of neurological diseases, such as Guillain-Barré syndrome, myelitis, meningoencephalitis, and congenital microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. MicroRNAs (miRNAs) are a group of small RNAs involved in the [...] Read more.

Zika virus (ZIKV) infections have caused a wide spectrum of neurological diseases, such as Guillain-Barré syndrome, myelitis, meningoencephalitis, and congenital microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. MicroRNAs (miRNAs) are a group of small RNAs involved in the regulation of a wide variety of cellular and physiological processes. In this study, we analyzed digital miRNA and mRNA profiles in ZIKV-infected primary mouse neurons using the nCounter technology. A total of 599 miRNAs and 770 mRNAs were examined. We demonstrate that ZIKV infection causes global downregulation of miRNAs with only few upregulated miRNAs. ZIKV-modulated miRNAs including miR-155, miR-203, miR-29a, and miR-124-3p are known to play critical role in flavivirus infection, anti-viral immunity and brain injury. ZIKV infection also results in downregulation of miRNA processing enzymes. In contrast, ZIKV infection induces dramatic upregulation of anti-viral, inflammatory and apoptotic genes. Furthermore, our data demonstrate an inverse correlation between ZIKV-modulated miRNAs and target host mRNAs induced by ZIKV. Biofunctional analysis revealed that ZIKV-modulated miRNAs and mRNAs regulate the pathways related to neurological development and neuroinflammatory responses. Functional studies targeting specific miRNA are warranted to develop therapeutics for the management of ZIKV neurological disease. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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21 pages, 3474 KiB

Open AccessArticle

The Roles of prM-E Proteins in Historical and Epidemic Zika Virus-mediated Infection and Neurocytotoxicity

by Ge Li, Sandra Bos, Konstantin A. Tsetsarkin, Alexander G. Pletnev, Philippe Desprès, Gilles Gadea and Richard Y. Zhao

Viruses 2019, 11(2), 157; https://doi.org/10.3390/v11020157 - 14 Feb 2019

Cited by 27 | Viewed by 5541

Abstract

The Zika virus (ZIKV) was first isolated in Africa in 1947. It was shown to be a mild virus that had limited threat to humans. However, the resurgence of the ZIKV in the most recent Brazil outbreak surprised us because it causes severe [...] Read more.

The Zika virus (ZIKV) was first isolated in Africa in 1947. It was shown to be a mild virus that had limited threat to humans. However, the resurgence of the ZIKV in the most recent Brazil outbreak surprised us because it causes severe human congenital and neurologic disorders including microcephaly in newborns and Guillain-Barré syndrome in adults. Studies showed that the epidemic ZIKV strains are phenotypically different from the historic strains, suggesting that the epidemic ZIKV has acquired mutations associated with the altered viral pathogenicity. However, what genetic changes are responsible for the changed viral pathogenicity remains largely unknown. One of our early studies suggested that the ZIKV structural proteins contribute in part to the observed virologic differences. The objectives of this study were to compare the historic African MR766 ZIKV strain with two epidemic Brazilian strains (BR15 and ICD) for their abilities to initiate viral infection and to confer neurocytopathic effects in the human brain’s SNB-19 glial cells, and further to determine which part of the ZIKV structural proteins are responsible for the observed differences. Our results show that the historic African (MR766) and epidemic Brazilian (BR15 and ICD) ZIKV strains are different in viral attachment to host neuronal cells, viral permissiveness and replication, as well as in the induction of cytopathic effects. The analysis of chimeric viruses, generated between the MR766 and BR15 molecular clones, suggests that the ZIKV E protein correlates with the viral attachment, and the C-prM region contributes to the permissiveness and ZIKV-induced cytopathic effects. The expression of adenoviruses, expressing prM and its processed protein products, shows that the prM protein and its cleaved Pr product, but not the mature M protein, induces apoptotic cell death in the SNB-19 cells. We found that the Pr region, which resides on the N-terminal side of prM protein, is responsible for prM-induced apoptotic cell death. Mutational analysis further identified four amino-acid residues that have an impact on the ability of prM to induce apoptosis. Together, the results of this study show that the difference of ZIKV-mediated viral pathogenicity, between the historic and epidemic strains, contributed in part the functions of the structural prM-E proteins. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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11 pages, 4383 KiB

Open AccessCommunication

Differential Zika Virus Infection of Testicular Cell Lines

by Luwanika Mlera and Marshall E. Bloom

Viruses 2019, 11(1), 42; https://doi.org/10.3390/v11010042 - 9 Jan 2019

Cited by 20 | Viewed by 5092

Abstract

Background: Zika virus is a mosquito-borne flavivirus responsible for recent outbreaks of epidemic proportions in Latin America. Sexual transmission of the virus has been reported in 13 countries and may be an important route of infection. Sexual transmission of ZIKV has mostly been [...] Read more.

Background: Zika virus is a mosquito-borne flavivirus responsible for recent outbreaks of epidemic proportions in Latin America. Sexual transmission of the virus has been reported in 13 countries and may be an important route of infection. Sexual transmission of ZIKV has mostly been male-to-female, and persistence of viral RNA in semen for up to 370 days has been recorded. The susceptibility to ZIKV of different testicular cell types merits investigation. Methods: We infected primary Sertoli cells, a primary testicular fibroblast Hs1.Tes, and 2 seminoma cell lines SEM-1 and TCam-2 cells with ZIKV Paraiba and the prototype ZIKV MR766 to evaluate their susceptibility and to look for viral persistence. A human neuroblastoma cell line SK-N-SH served as a control cell type. Results: Both virus strains were able to replicate in all cell lines tested, but ZIKV MR766 attained higher titers. Initiation of viral persistence by ZIKV Paraiba was observed in Sertoli, Hs1.Tes, SEM-1 and TCam-2 cells, but was of limited duration due to delayed cell death. ZIKV MR766 persisted only in Hs1.Tes and Sertoli cells, and persistence was also limited. In contrast, SK-N-SH cells were killed by both ZIKV MR766 and ZIKV Paraiba and persistence could not be established in these cells. Conclusions: ZIKV prototype strain MR766 and the clinically relevant Paraiba strain replicated in several testicular cell types. Persistence of ZIKV MR766 was only observed in Hs1.Tes and Sertoli cells, but the persistence did not last more than 3 or 4 passages, respectively. ZIKV Paraiba persisted in TCam-2, Hs1.Tes, Sertoli and SEM-1 cells for up to 5 passages, depending on cell type. TCam-2 cells appeared to clear persistent infection by ZIKV Paraiba. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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17 pages, 11363 KiB

Open AccessArticle

The Oxysterol 7-Ketocholesterol Reduces Zika Virus Titers in Vero Cells and Human Neurons

by Katherine A. Willard, Christina L. Elling, Steven L. Stice and Melinda A. Brindley

Viruses 2019, 11(1), 20; https://doi.org/10.3390/v11010020 - 30 Dec 2018

Cited by 21 | Viewed by 4393

Abstract

Zika virus (ZIKV) is an emerging flavivirus responsible for a major epidemic in the Americas beginning in 2015. ZIKV associated with maternal infection can lead to neurological disorders in newborns, including microcephaly. Although there is an abundance of research examining the neurotropism of [...] Read more.

Zika virus (ZIKV) is an emerging flavivirus responsible for a major epidemic in the Americas beginning in 2015. ZIKV associated with maternal infection can lead to neurological disorders in newborns, including microcephaly. Although there is an abundance of research examining the neurotropism of ZIKV, we still do not completely understand the mechanism by which ZIKV targets neural cells or how to limit neural cell infection. Recent research suggests that flaviviruses, including ZIKV, may hijack the cellular autophagy pathway to benefit their replication. Therefore, we hypothesized that ZIKV replication would be impacted when infected cells were treated with compounds that target the autophagy pathway. We screened a library of 94 compounds known to affect autophagy in both mammalian and insect cell lines. A subset of compounds that inhibited ZIKV replication without affecting cellular viability were tested for their ability to limit ZIKV replication in human neurons. From this second screen, we identified one compound, 7-ketocholesterol (7-KC), which inhibited ZIKV replication in neurons without significantly affecting neuron viability. Interestingly, 7-KC induces autophagy, which would be hypothesized to increase ZIKV replication, yet it decreased virus production. Time-of-addition experiments suggest 7-KC inhibits ZIKV replication late in the replication cycle. While 7-KC did not inhibit RNA replication, it decreased the number of particles in the supernatant and the relative infectivity of the released particles, suggesting it interferes with particle budding, release from the host cell, and particle integrity. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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13 pages, 1092 KiB

Open AccessArticle

Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus

by Chaker El Kalamouni, Etienne Frumence, Sandra Bos, Jonathan Turpin, Brice Nativel, Wissal Harrabi, David A. Wilkinson, Olivier Meilhac, Gilles Gadea, Philippe Desprès, Pascale Krejbich-Trotot and Wildriss Viranaïcken

Viruses 2019, 11(1), 2; https://doi.org/10.3390/v11010002 - 20 Dec 2018

Cited by 39 | Viewed by 5332

Abstract

Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and [...] Read more.

Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and the dengue virus by inhibiting viral growth. It has been reported that HO-1 displays antiviral activity against the Zika virus (ZIKV) but the mechanisms of viral inhibition remain largely unknown. Using a ZIKV RNA replicon with the Green Fluorescent Protein (GFP) as a reporter protein, we were able to show that HO-1 expression resulted in the inhibition of viral RNA replication. Conversely, we observed a decrease in HO-1 expression in cells replicating the ZIKV RNA replicon. The study of human cells infected with ZIKV showed that the HO-1 expression level was significantly lower once viral replication was established, thereby limiting the antiviral effect of HO-1. Our work highlights the capacity of ZIKV to thwart the anti-replicative activity of HO-1 in human cells. Therefore, the modulation of HO-1 as a novel therapeutic strategy against ZIKV infection may display limited effect. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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17 pages, 2031 KiB

Open AccessArticle

Contemporary Zika Virus Isolates Induce More dsRNA and Produce More Negative-Strand Intermediate in Human Astrocytoma Cells

by Trisha R. Barnard, Maaran M. Rajah and Selena M. Sagan

Viruses 2018, 10(12), 728; https://doi.org/10.3390/v10120728 - 19 Dec 2018

Cited by 16 | Viewed by 4946

Abstract

The recent emergence and rapid geographic expansion of Zika virus (ZIKV) poses a significant challenge for public health. Although historically causing only mild febrile illness, recent ZIKV outbreaks have been associated with more severe neurological complications, such as Guillain-Barré syndrome and fetal microcephaly. [...] Read more.

The recent emergence and rapid geographic expansion of Zika virus (ZIKV) poses a significant challenge for public health. Although historically causing only mild febrile illness, recent ZIKV outbreaks have been associated with more severe neurological complications, such as Guillain-Barré syndrome and fetal microcephaly. Here we demonstrate that two contemporary (2015) ZIKV isolates from Puerto Rico and Brazil may have increased replicative fitness in human astrocytoma cells. Over a single infectious cycle, the Brazilian isolate replicates to higher titers and induces more severe cytopathic effects in human astrocytoma cells than the historical African reference strain or an early Asian lineage isolate. In addition, both contemporary isolates induce significantly more double-stranded RNA in infected astrocytoma cells, despite similar numbers of infected cells across isolates. Moreover, when we quantified positive- and negative-strand viral RNA, we found that the Asian lineage isolates displayed substantially more negative-strand replicative intermediates than the African lineage isolate in human astrocytoma cells. However, over multiple rounds of infection, the contemporary ZIKV isolates appear to be impaired in cell spread, infecting a lower proportion of cells at a low MOI despite replicating to similar or higher titers. Taken together, our data suggests that contemporary ZIKV isolates may have evolved mechanisms that allow them to replicate with increased efficiency in certain cell types, thereby highlighting the importance of cell-intrinsic factors in studies of viral replicative fitness. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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22 pages, 4515 KiB

Open AccessArticle

Simultaneous Detection of Different Zika Virus Lineages via Molecular Computation in a Point-of-Care Assay

by Sanchita Bhadra, Miguel A. Saldaña, Hannah Grace Han, Grant L. Hughes and Andrew D. Ellington

Viruses 2018, 10(12), 714; https://doi.org/10.3390/v10120714 - 14 Dec 2018

Cited by 9 | Viewed by 5803

Abstract

We have developed a generalizable “smart molecular diagnostic” capable of accurate point-of-care (POC) detection of variable nucleic acid targets. Our isothermal assay relies on multiplex execution of four loop-mediated isothermal amplification reactions, with primers that are degenerate and redundant, thereby increasing the breadth [...] Read more.

We have developed a generalizable “smart molecular diagnostic” capable of accurate point-of-care (POC) detection of variable nucleic acid targets. Our isothermal assay relies on multiplex execution of four loop-mediated isothermal amplification reactions, with primers that are degenerate and redundant, thereby increasing the breadth of targets while reducing the probability of amplification failure. An easy-to-read visual answer is computed directly by a multi-input Boolean OR logic gate (gate output is true if either one or more gate inputs is true) signal transducer that uses degenerate strand exchange probes to assess any combination of amplicons. We demonstrate our methodology by using the same assay to detect divergent Asian and African lineages of the evolving Zika virus (ZIKV), while maintaining selectivity against non-target viruses. Direct analysis of biological specimens proved possible, with crudely macerated ZIKV-infected Aedes aegypti mosquitoes being identified with 100% specificity and sensitivity. The ease-of-use with minimal instrumentation, broad programmability, and built-in fail-safe reliability make our smart molecular diagnostic attractive for POC use. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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16 pages, 3809 KiB

Open AccessArticle

Tet-Inducible Production of Infectious Zika Virus from the Full-Length cDNA Clones of African- and Asian-Lineage Strains

by Lizhou Zhang, Wei Ji, Shuang Lyu, Luhua Qiao and Guangxiang Luo

Viruses 2018, 10(12), 700; https://doi.org/10.3390/v10120700 - 9 Dec 2018

Cited by 5 | Viewed by 4045

Abstract

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as an important human viral pathogen, causing congenital malformation including microcephaly among infants born to mothers infected with the virus during pregnancy. Phylogenetic analysis suggested that ZIKV can be classified into African and [...] Read more.

Zika virus (ZIKV) is a mosquito-borne flavivirus that has emerged as an important human viral pathogen, causing congenital malformation including microcephaly among infants born to mothers infected with the virus during pregnancy. Phylogenetic analysis suggested that ZIKV can be classified into African and Asian lineages. In this study, we have developed a stable plasmid-based reverse genetic system for robust production of both ZIKV prototype African-lineage MR766 and clinical Asian-lineage FSS13025 strains using a tetracycline (Tet)-controlled gene expression vector. Transcription of the full-length ZIKV RNA is under the control of the Tet-responsive P_tight promoter at the 5′ end and an antigenomic ribozyme of hepatitis delta virus at the 3′ end. The transcription of infectious ZIKV RNA genome was efficiently induced by doxycycline. This novel ZIKV reverse genetics system will be valuable for the study of molecular viral pathogenesis of ZIKV and the development of new vaccines against ZIKV infection. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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11 pages, 3246 KiB

Open AccessArticle

An Evolutionary Insight into Zika Virus Strains Isolated in the Latin American Region

by Diego Simón, Alvaro Fajardo, Pilar Moreno, Gonzalo Moratorio and Juan Cristina

Viruses 2018, 10(12), 698; https://doi.org/10.3390/v10120698 - 8 Dec 2018

Cited by 9 | Viewed by 3603

Abstract

Zika virus (ZIKV) is an emerging pathogen member of the Flaviviridae family. ZIKV has spread rapidly in the Latin American region, causing hundreds of thousands of cases of ZIKV disease, as well as microcephaly in congenital infections. Detailed studies on the pattern of [...] Read more.

Zika virus (ZIKV) is an emerging pathogen member of the Flaviviridae family. ZIKV has spread rapidly in the Latin American region, causing hundreds of thousands of cases of ZIKV disease, as well as microcephaly in congenital infections. Detailed studies on the pattern of evolution of ZIKV strains have been extremely important to our understanding of viral survival, fitness, and evasion of the host’s immune system. For these reasons, we performed a comprehensive phylogenetic analysis of ZIKV strains recently isolated in the Americas. The results of these studies revealed evidence of diversification of ZIKV strains circulating in the Latin American region into at least five different genetic clusters. This diversification was also reflected in the different trends in dinucleotide bias and codon usage variation. Amino acid substitutions were found in E and prM proteins of the ZIKV strains isolated in this region, revealing the presence of novel genetic variants circulating in Latin America. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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16 pages, 2933 KiB

Open AccessArticle

Characterizing the Different Effects of Zika Virus Infection in Placenta and Microglia Cells

by Maria del Pilar Martinez Viedma and Brett E. Pickett

Viruses 2018, 10(11), 649; https://doi.org/10.3390/v10110649 - 18 Nov 2018

Cited by 19 | Viewed by 5275

Abstract

Zika virus (ZIKV) is a neuropathic virus that causes serious neurological abnormalities such as Guillain-Barre syndrome in adults and congenital Zika syndrome (CZS) in fetuses, which makes it an important concern for global human health. A catalogue of cells that support ZIKV replication, [...] Read more.

Zika virus (ZIKV) is a neuropathic virus that causes serious neurological abnormalities such as Guillain-Barre syndrome in adults and congenital Zika syndrome (CZS) in fetuses, which makes it an important concern for global human health. A catalogue of cells that support ZIKV replication, pathogenesis, and/or the persistence of the virus still remains unknown. Here, we studied the behavior of the virus in human placenta (JEG-3) and human microglia (HMC3) cell lines in order to better understand how different host tissues respond during infection. We quantified the host transcriptional response to ZIKV infection in both types of cells at 24 and 72 h post-infection. A panel of 84 genes that are involved in the innate or adaptive immune responses was used to quantify differential expression in both cell lines. HMC3 cells showed a unique set of significant differentially expressed genes (DEGs) compared with JEG-3 cells at both time points. Subsequent analysis of these data using modern pathway analysis methods revealed that the TLR7/8 pathway was strongly inhibited in HMC3 cells, while it was activated in JEG-3 cells during virus infection. The disruption of these pathways was subsequently confirmed with specific small interfering RNA (siRNA) experiments that characterize their role in the viral life cycle, and may partially explain why ZIKV infection in placental tissue contributes to extreme neurological problems in a developing fetus. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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12 pages, 2243 KiB

Open AccessArticle

Development and Characterization of Double-Antibody Sandwich ELISA for Detection of Zika Virus Infection

by Liding Zhang, Xuewei Du, Congjie Chen, Zhixin Chen, Li Zhang, Qinqin Han, Xueshan Xia, Yuzhu Song and Jinyang Zhang

Viruses 2018, 10(11), 634; https://doi.org/10.3390/v10110634 - 15 Nov 2018

Cited by 27 | Viewed by 6008

Abstract

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defect and Guillain−Barré syndrome during pregnancy. Although, several molecular diagnostic methods have been developed to detect the ZIKV, these methods pose challenges as they cannot detect early [...] Read more.

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defect and Guillain−Barré syndrome during pregnancy. Although, several molecular diagnostic methods have been developed to detect the ZIKV, these methods pose challenges as they cannot detect early viral infection. Furthermore, these methods require the extraction of RNA, which is easy to contaminate. Nonstructural protein 1 (NS1) is an important biomarker for early diagnosis of the virus, and the detection methods associated with the NS1 protein have recently been reported. The aim of this study was to develop a rapid and sensitive detection method for the detection of the ZIKV based on the NS1 protein. The sensitivity of this method is 120 ng mL⁻¹ and it detected the ZIKV in the supernatant and lysates of Vero and BHK cells, as well as the sera of tree shrews infected with the ZIKV. Without the isolation of the virus and the extraction of the RNA, our method can be used as a primary screening test as opposed to other diagnosis methods that detect the ZIKV. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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16 pages, 3397 KiB

Open AccessArticle

Persistence and Intra-Host Genetic Evolution of Zika Virus Infection in Symptomatic Adults: A Special View in the Male Reproductive System

by Danielle B. L. Oliveira, Giuliana S. Durigon, Érica A. Mendes, Jason T. Ladner, Robert Andreata-Santos, Danielle B. Araujo, Viviane F. Botosso, Nicholas D. Paola, Daniel F. L. Neto, Marielton P. Cunha, Carla T. Braconi, Rúbens P. S. Alves, Monica R. Jesus, Lennon R. Pereira, Stella R. Melo, Flávio S. Mesquita, Vanessa B. Silveira, Luciano M. Thomazelli, Silvana R. Favoretto, Franciane B. Almonfrey, Regina C. R. M. Abdulkader, Joel M. Gabrili, Denise V. Tambourgi, Sérgio F. Oliveira, Karla Prieto, Michael R. Wiley, Luís C. S. Ferreira, Marcos V. Silva, Gustavo F. Palacios, Paolo M. A. Zanotto and Edison L. Durigon Show full author list Hide full author list

Viruses 2018, 10(11), 615; https://doi.org/10.3390/v10110615 - 7 Nov 2018

Cited by 32 | Viewed by 5826

Abstract

We followed the presence of Zika virus (ZIKV) in four healthy adults (two men and two women), for periods ranging from 78 to 298 days post symptom onset. The patients were evaluated regarding the presence of the virus in different body fluids (blood, [...] Read more.

We followed the presence of Zika virus (ZIKV) in four healthy adults (two men and two women), for periods ranging from 78 to 298 days post symptom onset. The patients were evaluated regarding the presence of the virus in different body fluids (blood, saliva, urine and semen), development of immune responses (including antibodies, cytokines and chemokines), and virus genetic variation within samples collected from semen and urine during the infection course. The analysis was focused primarily on the two male patients who shed the virus for up to 158 days after the initial symptoms. ZIKV particles were detected in the spermatozoa cytoplasm and flagella, in immature sperm cells and could also be isolated from semen in cell culture, confirming that the virus is able to preserve integrity and infectivity during replication in the male reproductive system (MRS). Despite the damage caused by ZIKV infection within the MRS, our data showed that ZIKV infection did not result in infertility at least in one of the male patients. This patient was able to conceive a child after the infection. We also detected alterations in the male genital cytokine milieu, which could play an important role in the replication and transmission of the virus which could considerably increase the risk of ZIKV sexual spread. In addition, full genome ZIKV sequences were obtained from several samples (mainly semen), which allowed us to monitor the evolution of the virus within a patient during the infection course. We observed genetic changes over time in consensus sequences and lower frequency intra-host single nucleotide variants (iSNV), that suggested independent compartmentalization of ZIKV populations in the reproductive and urinary systems. Altogether, the present observations confirm the risks associated with the long-term replication and shedding of ZIKV in the MRS and help to elucidate patterns of intra-host genetic evolution during long term replication of the virus. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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15 pages, 2343 KiB

Open AccessArticle

Strain-Dependent Consequences of Zika Virus Infection and Differential Impact on Neural Development

by Forrest T. Goodfellow, Katherine A. Willard, Xian Wu, Shelley Scoville, Steven L. Stice and Melinda A. Brindley

Viruses 2018, 10(10), 550; https://doi.org/10.3390/v10100550 - 9 Oct 2018

Cited by 33 | Viewed by 5188

Abstract

Maternal infection with Zika virus (ZIKV) during pregnancy can result in neonatal abnormalities, including neurological dysfunction and microcephaly. Experimental models of congenital Zika syndrome identified neural progenitor cells as a target of viral infection. Neural progenitor cells are responsible for populating the developing [...] Read more.

Maternal infection with Zika virus (ZIKV) during pregnancy can result in neonatal abnormalities, including neurological dysfunction and microcephaly. Experimental models of congenital Zika syndrome identified neural progenitor cells as a target of viral infection. Neural progenitor cells are responsible for populating the developing central nervous system with neurons and glia. Neural progenitor dysfunction can lead to severe birth defects, namely, lissencephaly, microcephaly, and cognitive deficits. For this study, the consequences of ZIKV infection in human pluripotent stem cell-derived neural progenitor (hNP) cells and neurons were evaluated. ZIKV isolates from Asian and African lineages displayed lineage-specific replication kinetics, cytopathic effects, and impacts on hNP function and neuronal differentiation. The currently circulating ZIKV isolates exhibit a unique profile of virulence, cytopathic effect, and impaired cellular functions that likely contribute to the pathological mechanism of congenital Zika syndrome. The authors found that infection with Asian-lineage ZIKV isolates impaired the proliferation and migration of hNP cells, and neuron maturation. In contrast, the African-lineage infections resulted in abrupt and extensive cell death. This work furthers the understanding of ZIKV-induced brain pathology. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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21 pages, 10263 KiB

Open AccessArticle

An Alanine-to-Valine Substitution in the Residue 175 of Zika Virus NS2A Protein Affects Viral RNA Synthesis and Attenuates the Virus In Vivo

by Silvia Márquez-Jurado, Aitor Nogales, Ginés Ávila-Pérez, Francisco J. Iborra, Luis Martínez-Sobrido and Fernando Almazán

Viruses 2018, 10(10), 547; https://doi.org/10.3390/v10100547 - 7 Oct 2018

Cited by 30 | Viewed by 5645

Abstract

The recent outbreaks of Zika virus (ZIKV), its association with Guillain–Barré syndrome and fetal abnormalities, and the lack of approved vaccines and antivirals, highlight the importance of developing countermeasures to combat ZIKV disease. In this respect, infectious clones constitute excellent tools to accomplish [...] Read more.

The recent outbreaks of Zika virus (ZIKV), its association with Guillain–Barré syndrome and fetal abnormalities, and the lack of approved vaccines and antivirals, highlight the importance of developing countermeasures to combat ZIKV disease. In this respect, infectious clones constitute excellent tools to accomplish these goals. However, flavivirus infectious clones are often difficult to work with due to the toxicity of some flavivirus sequences in bacteria. To bypass this problem, several alternative approaches have been applied for the generation of ZIKV clones including, among others, in vitro ligation, insertions of introns and using infectious subgenomic amplicons. Here, we report a simple and novel DNA-launched approach based on the use of a bacterial artificial chromosome (BAC) to generate a cDNA clone of Rio Grande do Norte Natal ZIKV strain. The sequence was identified from the brain tissue of an aborted fetus with microcephaly. The BAC clone was fully stable in bacteria and the infectious virus was efficiently recovered in Vero cells through direct delivery of the cDNA clone. The rescued virus yielded high titers in Vero cells and was pathogenic in a validated mouse model (A129 mice) of ZIKV infection. Furthermore, using this infectious clone we have generated a mutant ZIKV containing a single amino acid substitution (A175V) in the NS2A protein that presented reduced viral RNA synthesis in cell cultures, was highly attenuated in vivo and induced fully protection against a lethal challenge with ZIKV wild-type. This BAC approach provides a stable and reliable reverse genetic system for ZIKV that will help to identify viral determinants of virulence and facilitate the development of vaccine and therapeutic strategies. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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10 pages, 1836 KiB

Open AccessCommunication

Fetal Brain Infection Is Not a Unique Characteristic of Brazilian Zika Viruses

by Yin Xiang Setoh, Nias Y. Peng, Eri Nakayama, Alberto A. Amarilla, Natalie A. Prow, Andreas Suhrbier and Alexander A. Khromykh

Viruses 2018, 10(10), 541; https://doi.org/10.3390/v10100541 - 3 Oct 2018

Cited by 14 | Viewed by 5126

Abstract

The recent emergence of Zika virus (ZIKV) in Brazil was associated with an increased number of fetal brain infections that resulted in a spectrum of congenital neurological complications known as congenital Zika syndrome (CZS). Herein, we generated de novo from sequence data an [...] Read more.

The recent emergence of Zika virus (ZIKV) in Brazil was associated with an increased number of fetal brain infections that resulted in a spectrum of congenital neurological complications known as congenital Zika syndrome (CZS). Herein, we generated de novo from sequence data an early Asian lineage ZIKV isolate (ZIKV-MY; Malaysia, 1966) not associated with microcephaly and compared the in vitro replication kinetics and fetal brain infection in interferon α/β receptor 1 knockout (IFNAR1^−/−) dams of this isolate and of a Brazilian isolate (ZIKV-Natal; Natal, 2015) unequivocally associated with microcephaly. The replication efficiencies of ZIKV-MY and ZIKV-Natal in A549 and Vero cells were similar, while ZIKV-MY replicated more efficiently in wild-type (WT) and IFNAR^−/− mouse embryonic fibroblasts. Viremias in IFNAR1^−/− dams were similar after infection with ZIKV-MY or ZIKV-Natal, and importantly, infection of fetal brains was also not significantly different. Thus, fetal brain infection does not appear to be a unique feature of Brazilian ZIKV isolates. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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18 pages, 1119 KiB

Open AccessArticle

The Effect of Permethrin Resistance on Aedes aegypti Transcriptome Following Ingestion of Zika Virus Infected Blood

by Liming Zhao, Barry W. Alto, Dongyoung Shin and Fahong Yu

Viruses 2018, 10(9), 470; https://doi.org/10.3390/v10090470 - 1 Sep 2018

Cited by 16 | Viewed by 5108

Abstract

Aedes aegypti (L.) is the primary vector of many emerging arboviruses. Insecticide resistance among mosquito populations is a consequence of the application of insecticides for mosquito control. We used RNA-sequencing to compare transcriptomes between permethrin resistant and susceptible strains of Florida Ae. aegypti [...] Read more.

Aedes aegypti (L.) is the primary vector of many emerging arboviruses. Insecticide resistance among mosquito populations is a consequence of the application of insecticides for mosquito control. We used RNA-sequencing to compare transcriptomes between permethrin resistant and susceptible strains of Florida Ae. aegypti in response to Zika virus infection. A total of 2459 transcripts were expressed at significantly different levels between resistant and susceptible Ae. aegypti. Gene ontology analysis placed these genes into seven categories of biological processes. The 863 transcripts were expressed at significantly different levels between the two mosquito strains (up/down regulated) more than 2-fold. Quantitative real-time PCR analysis was used to validate the Zika-infection response. Our results suggested a highly overexpressed P450, with AAEL014617 and AAEL006798 as potential candidates for the molecular mechanism of permethrin resistance in Ae. aegypti. Our findings indicated that most detoxification enzymes and immune system enzymes altered their gene expression between the two strains of Ae. aegypti in response to Zika virus infection. Understanding the interactions of arboviruses with resistant mosquito vectors at the molecular level allows for the possible development of new approaches in mitigating arbovirus transmission. This information sheds light on Zika-induced changes in insecticide resistant Ae. aegypti with implications for mosquito control strategies. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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28 pages, 7627 KiB

Open AccessArticle

Functional Genomics and Immunologic Tools: The Impact of Viral and Host Genetic Variations on the Outcome of Zika Virus Infection

by Sang-Im Yun, Byung-Hak Song, Jordan C. Frank, Justin G. Julander, Aaron L. Olsen, Irina A. Polejaeva, Christopher J. Davies, Kenneth L. White and Young-Min Lee

Viruses 2018, 10(8), 422; https://doi.org/10.3390/v10080422 - 11 Aug 2018

Cited by 13 | Viewed by 5432

Abstract

Zika virus (ZIKV) causes no-to-mild symptoms or severe neurological disorders. To investigate the importance of viral and host genetic variations in determining ZIKV infection outcomes, we created three full-length infectious cDNA clones as bacterial artificial chromosomes for each of three spatiotemporally distinct and [...] Read more.

Zika virus (ZIKV) causes no-to-mild symptoms or severe neurological disorders. To investigate the importance of viral and host genetic variations in determining ZIKV infection outcomes, we created three full-length infectious cDNA clones as bacterial artificial chromosomes for each of three spatiotemporally distinct and genetically divergent ZIKVs: MR-766 (Uganda, 1947), P6-740 (Malaysia, 1966), and PRVABC-59 (Puerto Rico, 2015). Using the three molecularly cloned ZIKVs, together with 13 ZIKV region-specific polyclonal antibodies covering nearly the entire viral protein-coding region, we made three conceptual advances: (i) We created a comprehensive genome-wide portrait of ZIKV gene products and their related species, with several previously undescribed gene products identified in the case of all three molecularly cloned ZIKVs. (ii) We found that ZIKV has a broad cell tropism in vitro, being capable of establishing productive infection in 16 of 17 animal cell lines from 12 different species, although its growth kinetics varied depending on both the specific virus strain and host cell line. More importantly, we identified one ZIKV-non-susceptible bovine cell line that has a block in viral entry but fully supports the subsequent post-entry steps. (iii) We showed that in mice, the three molecularly cloned ZIKVs differ in their neuropathogenicity, depending on the particular combination of viral and host genetic backgrounds, as well as in the presence or absence of type I/II interferon signaling. Overall, our findings demonstrate the impact of viral and host genetic variations on the replication kinetics and neuropathogenicity of ZIKV and provide multiple avenues for developing and testing medical countermeasures against ZIKV. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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9 pages, 228 KiB

Open AccessArticle

Comparative Evaluation of Indirect Immunofluorescence and NS-1-Based ELISA to Determine Zika Virus-Specific IgM

by Fernando De Ory, María Paz Sánchez-Seco, Ana Vázquez, María Dolores Montero, Elena Sulleiro, Miguel J. Martínez, Lurdes Matas, Francisco J. Merino and Working Group for the Study of Zika Virus Infections

Viruses 2018, 10(7), 379; https://doi.org/10.3390/v10070379 - 19 Jul 2018

Cited by 12 | Viewed by 4522

Abstract

Differential diagnosis of the Zika virus (ZIKV) is hampered by cross-reactivity with other flaviviruses, mainly dengue viruses. The aim of this study was to compare two commercial methods for detecting ZIKV immunoglobulin M (IgM), an indirect immunofluorescence (IIF) and an enzyme immunoassay (ELISA), [...] Read more.

Differential diagnosis of the Zika virus (ZIKV) is hampered by cross-reactivity with other flaviviruses, mainly dengue viruses. The aim of this study was to compare two commercial methods for detecting ZIKV immunoglobulin M (IgM), an indirect immunofluorescence (IIF) and an enzyme immunoassay (ELISA), using the non-structural (NS) 1 protein as an antigen, both from EuroImmun, Germany. In total, 255 serum samples were analyzed, 203 of which showed laboratory markers of ZIKV infections (PCR-positive in serum and/or in urine and/or positive or indeterminate specific IgM). When tested with IIF, 163 samples were IgM-positive, while 13 samples were indeterminate and 78 were negative. When IIF-positive samples were tested using ELISA, we found 61 positive results, 14 indeterminate results, and 88 negative results. Among the indeterminate cases tested with IIF, ELISA analysis found two positive, two indeterminate, and nine negative results. Finally, 74 of the 78 IIF-negative samples proved also to be negative using ELISA. For the calculations, all indeterminate results were considered to be positive. The agreement, sensitivity, and specificity between ELISA and IIF were 60.2%, 44.9%, and 94.9%, respectively. Overall, 101 samples showed discrepant results; these samples were finally classified on the basis of other ZIKV diagnostic approaches (PCR-positive in serum and/or in urine, IgG determinations using IIF or ELISA, and ZIKV Plaque Reduction Neutralization test—positive), when available. A final classification of 228 samples was possible; 126 of them were positive and 102 were negative. The corresponding values of agreement, sensitivity, and specificity of IIF were 86.0%, 96.8%, and 72.5%, respectively. The corresponding figures for ELISA were 81.1%, 65.9%, and 100%, respectively. The ELISA and IIF methods are both adequate approaches for detecting ZIKV-specific IgM. However, considering their respective weaknesses (low sensitivity in ELISA and low specificity in IIF), serological results must be considered jointly with other laboratory results. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

17 pages, 2651 KiB

Open AccessArticle

A Reverse Genetics System for Zika Virus Based on a Simple Molecular Cloning Strategy

by Maximilian Münster, Anna Płaszczyca, Mirko Cortese, Christopher John Neufeldt, Sarah Goellner, Gang Long and Ralf Bartenschlager

Viruses 2018, 10(7), 368; https://doi.org/10.3390/v10070368 - 12 Jul 2018

Cited by 36 | Viewed by 7594

Abstract

The Zika virus (ZIKV) has recently attracted major research interest as infection was unexpectedly associated with neurological manifestations in developing foetuses and with Guillain-Barré syndrome in infected adults. Understanding the underlying molecular mechanisms requires reverse genetic systems, which allow manipulation of infectious cDNA [...] Read more.

The Zika virus (ZIKV) has recently attracted major research interest as infection was unexpectedly associated with neurological manifestations in developing foetuses and with Guillain-Barré syndrome in infected adults. Understanding the underlying molecular mechanisms requires reverse genetic systems, which allow manipulation of infectious cDNA clones at will. In the case of flaviviruses, to which ZIKV belongs, several reports have indicated that the construction of full-length cDNA clones is difficult due to toxicity during plasmid amplification in Escherichia coli. Toxicity of flaviviral cDNAs has been linked to the activity of cryptic prokaryotic promoters within the region encoding the structural proteins leading to spurious transcription and expression of toxic viral proteins. Here, we employ an approach based on in silico prediction and mutational silencing of putative promoters to generate full-length cDNA clones of the historical MR766 strain and the contemporary French Polynesian strain H/PF/2013 of ZIKV. While for both strains construction of full-length cDNA clones has failed in the past, we show that our approach generates cDNA clones that are stable on single bacterial plasmids and give rise to infectious viruses with properties similar to those generated by other more complex assembly strategies. Further, we generate luciferase and fluorescent reporter viruses as well as sub-genomic replicons that are fully functional and suitable for various research and drug screening applications. Taken together, this study confirms that in silico prediction and silencing of cryptic prokaryotic promoters is an efficient strategy to generate full-length cDNA clones of flaviviruses and reports novel tools that will facilitate research on ZIKV biology and development of antiviral strategies. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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15 pages, 854 KiB

Open AccessArticle

Detection of Specific ZIKV IgM in Travelers Using a Multiplexed Flavivirus Microsphere Immunoassay

by Carmel T. Taylor, Ian M. Mackay, Jamie L. McMahon, Sarah L. Wheatley, Peter R. Moore, Mitchell J. Finger, Glen R. Hewitson and Frederick A. Moore

Viruses 2018, 10(5), 253; https://doi.org/10.3390/v10050253 - 12 May 2018

Cited by 13 | Viewed by 5883

Abstract

Zika virus (ZIKV) has spread widely in the Pacific and recently throughout the Americas. Unless detected by RT-PCR, confirming an acute ZIKV infection can be challenging. We developed and validated a multiplexed flavivirus immunoglobulin M (IgM) microsphere immunoassay (flaviMIA) which can differentiate ZIKV-specific [...] Read more.

Zika virus (ZIKV) has spread widely in the Pacific and recently throughout the Americas. Unless detected by RT-PCR, confirming an acute ZIKV infection can be challenging. We developed and validated a multiplexed flavivirus immunoglobulin M (IgM) microsphere immunoassay (flaviMIA) which can differentiate ZIKV-specific IgM from that due to other flavivirus infections in humans. The flaviMIA bound 12 inactivated flavivirus antigens, including those from ZIKV and yellow fever virus (YFV), to distinct anti-flavivirus antibody coupled beads. These beads were used to interrogate sera from patients with suspected ZIKV infection following travel to relevant countries. FlaviMIA results were validated by comparison to the ZIKV plaque reduction neutralization test (PRNT). The results highlight the complexity of serological ZIKV diagnosis, particularly in patients previously exposed to or vaccinated against other flaviviruses. We confirmed 99 patients with ZIKV infection by a combination of RT-PCR and serology. Importantly, ZIKV antibodies could be discriminated from those ascribed to other flavivirus infections. Serological results were sometimes confounded by the presence of pre-existing antibodies attributed to previous flavivirus infection or vaccination. Where RT-PCR results were negative, testing of appropriately timed paired sera was necessary to demonstrate seroconversion or differentiation of recent from past infection with or exposure to ZIKV. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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16 pages, 2251 KiB

Open AccessArticle

Comparative Pathogenesis of Asian and African-Lineage Zika Virus in Indian Rhesus Macaque’s and Development of a Non-Human Primate Model Suitable for the Evaluation of New Drugs and Vaccines

by Jonathan O. Rayner, Raj Kalkeri, Scott Goebel, Zhaohui Cai, Brian Green, Shuling Lin, Beth Snyder, Kimberly Hagelin, Kevin B. Walters and Fusataka Koide

Viruses 2018, 10(5), 229; https://doi.org/10.3390/v10050229 - 1 May 2018

Cited by 25 | Viewed by 5712

Abstract

The establishment of a well characterized non-human primate model of Zika virus (ZIKV) infection is critical for the development of medical interventions. In this study, challenging Indian rhesus macaques (IRMs) with ZIKV strains of the Asian lineage resulted in dose-dependent peak viral loads [...] Read more.

The establishment of a well characterized non-human primate model of Zika virus (ZIKV) infection is critical for the development of medical interventions. In this study, challenging Indian rhesus macaques (IRMs) with ZIKV strains of the Asian lineage resulted in dose-dependent peak viral loads between days 2 and 5 post infection and a robust immune response which protected the animals from homologous and heterologous re-challenge. In contrast, viremia in IRMs challenged with an African lineage strain was below the assay’s lower limit of quantitation, and the immune response was insufficient to protect from re-challenge. These results corroborate previous observations but are contrary to reports using other African strains, obviating the need for additional studies to elucidate the variables contributing to the disparities. Nonetheless, the utility of an Asian lineage ZIKV IRM model for countermeasure development was verified by vaccinating animals with a formalin inactivated reference vaccine and demonstrating sterilizing immunity against a subsequent subcutaneous challenge. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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14 pages, 10575 KiB

Open AccessArticle

Inhibition of Zika Virus Replication by Silvestrol

by Fabian Elgner, Catarina Sabino, Michael Basic, Daniela Ploen, Arnold Grünweller and Eberhard Hildt

Viruses 2018, 10(4), 149; https://doi.org/10.3390/v10040149 - 27 Mar 2018

Cited by 55 | Viewed by 7995

Abstract

The Zika virus (ZIKV) outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the [...] Read more.

The Zika virus (ZIKV) outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the plant Aglaia foveolata was found to have very potent antiviral effects against the (−)-strand RNA-virus Ebola virus as well as against Corona- and Picornaviruses with a (+)-strand RNA-genome. This antiviral activity is based on the impaired translation of viral RNA by the inhibition of the DEAD-box RNA helicase eukaryotic initiation factor-4A (eIF4A) which is required to unwind structured 5´-untranslated regions (5′-UTRs) of several proto-oncogenes and thereby facilitate their translation. Zika virus is a flavivirus with a positive-stranded RNA-genome harboring a 5′-capped UTR with distinct secondary structure elements. Therefore, we investigated the effects of silvestrol on ZIKV replication in A549 cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A549 cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol. Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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Review

Jump to: Editorial, Research

16 pages, 263 KiB

Open AccessReview

Suppression of Type I Interferon Signaling by Flavivirus NS5

by Stephanie Thurmond, Boxiao Wang, Jikui Song and Rong Hai

Viruses 2018, 10(12), 712; https://doi.org/10.3390/v10120712 - 14 Dec 2018

Cited by 39 | Viewed by 4999

Abstract

Type I interferon (IFN-I) is the first line of mammalian host defense against viral infection. To counteract this, the flaviviruses, like other viruses, have encoded a variety of antagonists, and use a multi-layered molecular defense strategy to establish their infections. Among the most [...] Read more.

Type I interferon (IFN-I) is the first line of mammalian host defense against viral infection. To counteract this, the flaviviruses, like other viruses, have encoded a variety of antagonists, and use a multi-layered molecular defense strategy to establish their infections. Among the most potent antagonists is non-structural protein 5 (NS5), which has been shown for all disease-causing flaviviruses to target different steps and players of the type I IFN signaling pathway. Here, we summarize the type I IFN antagonist mechanisms used by flaviviruses with a focus on the role of NS5 in regulating one key regulator of type I IFN, signal transducer and activator of transcription 2 (STAT2). Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

13 pages, 406 KiB

Open AccessReview

Recent Advances in Zika Virus Vaccines

by Himanshu Garg, Tugba Mehmetoglu-Gurbuz and Anjali Joshi

Viruses 2018, 10(11), 631; https://doi.org/10.3390/v10110631 - 14 Nov 2018

Cited by 39 | Viewed by 4966

Abstract

The recent outbreaks of Zika virus (ZIKV) infections and associated microcephaly in newborns has resulted in an unprecedented effort by researchers to target this virus. Significant advances have been made in developing vaccine candidates, treatment strategies and diagnostic assays in a relatively short [...] Read more.

The recent outbreaks of Zika virus (ZIKV) infections and associated microcephaly in newborns has resulted in an unprecedented effort by researchers to target this virus. Significant advances have been made in developing vaccine candidates, treatment strategies and diagnostic assays in a relatively short period of time. Being a preventable disease, the first line of defense against ZIKV would be to vaccinate the highly susceptible target population, especially pregnant women. Along those lines, several vaccine candidates including purified inactivated virus (PIV), live attenuated virus (LAV), virus like particles (VLP), DNA, modified RNA, viral vectors and subunit vaccines have been in the pipeline with several advancing to clinical trials. As the primary objective of Zika vaccination is the prevention of vertical transmission of the virus to the unborn fetus, the safety and efficacy requirements for this vaccine remain unique when compared to other diseases. This review will discuss these recent advances in the field of Zika vaccine development. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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22 pages, 1614 KiB

Open AccessReview

Reverse Genetic Approaches for the Generation of Recombinant Zika Virus

by Ginés Ávila-Pérez, Aitor Nogales, Verónica Martín, Fernando Almazán and Luis Martínez-Sobrido

Viruses 2018, 10(11), 597; https://doi.org/10.3390/v10110597 - 31 Oct 2018

Cited by 29 | Viewed by 11441

Abstract

Zika virus (ZIKV) is an emergent mosquito-borne member of the Flaviviridae family that was responsible for a recent epidemic in the Americas. ZIKV has been associated with severe clinical complications, including neurological disorder such as Guillain-Barré syndrome in adults and severe fetal abnormalities [...] Read more.

Zika virus (ZIKV) is an emergent mosquito-borne member of the Flaviviridae family that was responsible for a recent epidemic in the Americas. ZIKV has been associated with severe clinical complications, including neurological disorder such as Guillain-Barré syndrome in adults and severe fetal abnormalities and microcephaly in newborn infants. Given the significance of these clinical manifestations, the development of tools and reagents to study the pathogenesis of ZIKV and to develop new therapeutic options are urgently needed. In this respect, the implementation of reverse genetic techniques has allowed the direct manipulation of the viral genome to generate recombinant (r)ZIKVs, which have provided investigators with powerful systems to answer important questions about the biology of ZIKV, including virus-host interactions, the mechanism of transmission and pathogenesis or the function of viral proteins. In this review, we will summarize the different reverse genetic strategies that have been implemented, to date, for the generation of rZIKVs and the applications of these platforms for the development of replicon systems or reporter-expressing viruses. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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30 pages, 2763 KiB

Open AccessReview

Research Models and Tools for the Identification of Antivirals and Therapeutics against Zika Virus Infection

by Marco P. Alves, Nathalie J. Vielle, Volker Thiel and Stephanie Pfaender

Viruses 2018, 10(11), 593; https://doi.org/10.3390/v10110593 - 30 Oct 2018

Cited by 15 | Viewed by 7433

Abstract

Zika virus recently re-emerged and caused global outbreaks mainly in Central Africa, Southeast Asia, the Pacific Islands and in Central and South America. Even though there is a declining trend, the virus continues to spread throughout different geographical regions of the world. Since [...] Read more.

Zika virus recently re-emerged and caused global outbreaks mainly in Central Africa, Southeast Asia, the Pacific Islands and in Central and South America. Even though there is a declining trend, the virus continues to spread throughout different geographical regions of the world. Since its re-emergence in 2015, massive advances have been made regarding our understanding of clinical manifestations, epidemiology, genetic diversity, genomic structure and potential therapeutic intervention strategies. Nevertheless, treatment remains a challenge as there is no licensed effective therapy available. This review focuses on the recent advances regarding research models, as well as available experimental tools that can be used for the identification and characterization of potential antiviral targets and therapeutic intervention strategies. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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20 pages, 1628 KiB

Open AccessReview

Ocular Manifestations of Emerging Flaviviruses and the Blood-Retinal Barrier

by Sneha Singh, Dustin Farr and Ashok Kumar

Viruses 2018, 10(10), 530; https://doi.org/10.3390/v10100530 - 28 Sep 2018

Cited by 53 | Viewed by 9012

Abstract

Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal [...] Read more.

Despite flaviviruses remaining the leading cause of systemic human infections worldwide, ocular manifestations of these mosquito-transmitted viruses are considered relatively uncommon in part due to under-reporting. However, recent outbreaks of Zika virus (ZIKV) implicated in causing multiple ocular abnormalities, such as conjunctivitis, retinal hemorrhages, chorioretinal atrophy, posterior uveitis, optic neuritis, and maculopathies, has rejuvenated a significant interest in understanding the pathogenesis of flaviviruses, including ZIKV, in the eye. In this review, first, we summarize the current knowledge of the major flaviviruses (Dengue, West Nile, Yellow Fever, and Japanese Encephalitis) reported to cause ocular manifestations in humans with emphasis on recent ZIKV outbreaks. Second, being an immune privilege organ, the eye is protected from systemic infections by the presence of blood-retinal barriers (BRB). Hence, we discuss how flaviviruses modulate retinal innate response and breach the protective BRB to cause ocular or retinal pathology. Finally, we describe recently identified infection signatures of ZIKV and discuss whether these system biology-predicted genes or signaling pathways (e.g., cellular metabolism) could contribute to the pathogenesis of ocular manifestations and assist in the development of ocular antiviral therapies against ZIKV and other flaviviruses. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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7 pages, 213 KiB

Open AccessReview

External Quality Assessment (EQA) for Molecular Diagnostics of Zika Virus: Experiences from an International EQA Programme, 2016–2018

by Oliver Donoso Mantke, Elaine McCulloch, Paul S. Wallace, Constanze Yue, Sally A. Baylis and Matthias Niedrig

Viruses 2018, 10(9), 491; https://doi.org/10.3390/v10090491 - 13 Sep 2018

Cited by 8 | Viewed by 4649

Abstract

Quality Control for Molecular Diagnostics (QCMD), an international provider for External Quality Assessment (EQA) programmes, has introduced a programme for molecular diagnostics of Zika virus (ZIKV) in 2016, which has been continuously offered to interested laboratories since that time. The EQA schemes provided [...] Read more.

Quality Control for Molecular Diagnostics (QCMD), an international provider for External Quality Assessment (EQA) programmes, has introduced a programme for molecular diagnostics of Zika virus (ZIKV) in 2016, which has been continuously offered to interested laboratories since that time. The EQA schemes provided from 2016 to 2018 revealed that 86.7% (92/106), 82.4% (89/108), and 88.2% (90/102) of the participating laboratories reported correct results for all samples, respectively in 2016, 2017, and 2018. The review of results indicated a need for improvement concerning analytical sensitivity and specificity of the test methods. Comparison with the outcomes of other EQA initiatives briefly summarized here show that continuous quality assurance is important to improve laboratory performance and to increase preparedness with reliable diagnostic assays for effective patient management, infection and outbreak control. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

18 pages, 1369 KiB

Open AccessReview

Host-Directed Antivirals: A Realistic Alternative to Fight Zika Virus

by Juan-Carlos Saiz, Nereida Jiménez de Oya, Ana-Belén Blázquez, Estela Escribano-Romero and Miguel A. Martín-Acebes

Viruses 2018, 10(9), 453; https://doi.org/10.3390/v10090453 - 24 Aug 2018

Cited by 38 | Viewed by 6278

Abstract

Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid [...] Read more.

Zika virus (ZIKV), a mosquito-borne flavivirus, was an almost neglected pathogen until its introduction in the Americas in 2015, where it has been responsible for a threat to global health, causing a great social and sanitary alarm due to its increased virulence, rapid spread, and an association with severe neurological and ophthalmological complications. Currently, no specific antiviral therapy against ZIKV is available, and treatments are palliative and mainly directed toward the relief of symptoms, such as fever and rash, by administering antipyretics, anti-histamines, and fluids for dehydration. Nevertheless, lately, search for antivirals has been a major aim in ZIKV investigations. To do so, screening of libraries from different sources, testing of natural compounds, and repurposing of drugs with known antiviral activity have allowed the identification of several antiviral candidates directed to both viral (structural proteins and enzymes) and cellular elements. Here, we present an updated review of current knowledge about anti-ZIKV strategies, focusing on host-directed antivirals as a realistic alternative to combat ZIKV infection. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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26 pages, 1495 KiB

Open AccessReview

Probing Molecular Insights into Zika Virus–Host Interactions

by Ina Lee, Sandra Bos, Ge Li, Shusheng Wang, Gilles Gadea, Philippe Desprès and Richard Y. Zhao

Viruses 2018, 10(5), 233; https://doi.org/10.3390/v10050233 - 2 May 2018

Cited by 67 | Viewed by 9734

Abstract

The recent Zika virus (ZIKV) outbreak in the Americas surprised all of us because of its rapid spread and association with neurologic disorders including fetal microcephaly, brain and ocular anomalies, and Guillain–Barré syndrome. In response to this global health crisis, unprecedented and world-wide [...] Read more.

The recent Zika virus (ZIKV) outbreak in the Americas surprised all of us because of its rapid spread and association with neurologic disorders including fetal microcephaly, brain and ocular anomalies, and Guillain–Barré syndrome. In response to this global health crisis, unprecedented and world-wide efforts are taking place to study the ZIKV-related human diseases. Much has been learned about this virus in the areas of epidemiology, genetic diversity, protein structures, and clinical manifestations, such as consequences of ZIKV infection on fetal brain development. However, progress on understanding the molecular mechanism underlying ZIKV-associated neurologic disorders remains elusive. To date, we still lack a good understanding of; (1) what virologic factors are involved in the ZIKV-associated human diseases; (2) which ZIKV protein(s) contributes to the enhanced viral pathogenicity; and (3) how do the newly adapted and pandemic ZIKV strains alter their interactions with the host cells leading to neurologic defects? The goal of this review is to explore the molecular insights into the ZIKV–host interactions with an emphasis on host cell receptor usage for viral entry, cell innate immunity to ZIKV, and the ability of ZIKV to subvert antiviral responses and to cause cytopathic effects. We hope this literature review will inspire additional molecular studies focusing on ZIKV–host Interactions. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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15 pages, 2331 KiB

Open AccessReview

Zika Virus in the Male Reproductive Tract

by Liesel Stassen, Charles W. Armitage, David J. Van der Heide, Kenneth W. Beagley and Francesca D. Frentiu

Viruses 2018, 10(4), 198; https://doi.org/10.3390/v10040198 - 16 Apr 2018

Cited by 46 | Viewed by 8896

Abstract

Arthropod-borne viruses (arboviruses) are resurging across the globe. Zika virus (ZIKV) has caused significant concern in recent years because it can lead to congenital malformations in babies and Guillain-Barré syndrome in adults. Unlike other arboviruses, ZIKV can be sexually transmitted and may persist [...] Read more.

Arthropod-borne viruses (arboviruses) are resurging across the globe. Zika virus (ZIKV) has caused significant concern in recent years because it can lead to congenital malformations in babies and Guillain-Barré syndrome in adults. Unlike other arboviruses, ZIKV can be sexually transmitted and may persist in the male reproductive tract. There is limited information regarding the impact of ZIKV on male reproductive health and fertility. Understanding the mechanisms that underlie persistent ZIKV infections in men is critical to developing effective vaccines and therapies. Mouse and macaque models have begun to unravel the pathogenesis of ZIKV infection in the male reproductive tract, with the testes and prostate gland implicated as potential reservoirs for persistent ZIKV infection. Here, we summarize current knowledge regarding the pathogenesis of ZIKV in the male reproductive tract, the development of animal models to study ZIKV infection at this site, and prospects for vaccines and therapeutics against persistent ZIKV infection. Full article

(This article belongs to the Special Issue New Advances on Zika Virus Research)

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