Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the sci...Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.展开更多
Objective:To characterize the infection patterns and growth characteristics of the Zika virus(ZIKV)strain JMB-185 from Indonesia in various mammalian cell lines.Methods:ZIKV was grown in human(A549,HEK293,HepG2,Huh7,J...Objective:To characterize the infection patterns and growth characteristics of the Zika virus(ZIKV)strain JMB-185 from Indonesia in various mammalian cell lines.Methods:ZIKV was grown in human(A549,HEK293,HepG2,Huh7,Jurkat,and THP-1)and non-human mammalian(RAW264.7,Vero,and Vero76)cell lines.Viral replication kinetics were measured using plaque assay,while intra-and extracellular viral RNA concentrations were assessed using RT-PCR.Flow cytometry was used to quantify the infected cells and cell viability was measured using an MTT assay.The ability of ZIKV to infect cell lines was visualized using a fluorescence immunostaining assay.Results:This ZIKV strain preferentially infected the lung,kidney,and liver cell lines A549,HEK293,Huh7,Vero,and Vero76,but not the immune cells Jurkat,RAW264.7,and THP-1.By contrast,the ZIKV showed no sign of infection in HepG2 cells,while maintaining viral titer over 3 days post-infection,with no infection recorded in immunostaining,no increase in viral RNA,and no indication of cell deterioration.Conclusions:The Indonesian ZIKV strain has a similar infection profile as other strains,except for its poor infectivity on HepG2 cells.Information on the growth characteristics of Indonesia ZIKV will help expand our understanding of the biology of ZIKV which will be useful for various applications including antiviral discovery.展开更多
Objectives To identify the 5'untranslated region of Zika virus(ZIKV 5'UTR)RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site(IRES)located...Objectives To identify the 5'untranslated region of Zika virus(ZIKV 5'UTR)RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site(IRES)located in ZIKV 5'UTR and virus production.Methods Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining,Subsequently,liquid chromatographytandem mass spectrometry(LC-MS/MS),bioinformatics analysis,and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR.Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production,respecitvely.Results tRSA RNA pull-down assay,LC-MS/MS,and Western blot analysis showed that polypyrimidine tractbinding protein(PTB)bound to the ZIKV 5'UTR.Furthermore,dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV(t=10.220,P<0.001),while PTB knockdown had the opposite effect(t=4.897,P<0.01).Additionally,virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer(t=6.400,P<0.01),whereas reducing PTB expression level weakened virus infectivity(t=5.055,P<0.01).Conclusion PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production.展开更多
Zika virus (ZIKV), a mosquito-borne flavivirus, has been associated with benign infections for decades. However, it has become a public health concern due to its association with severe fetal and neurological complica...Zika virus (ZIKV), a mosquito-borne flavivirus, has been associated with benign infections for decades. However, it has become a public health concern due to its association with severe fetal and neurological complications. Although many efforts have been made to control ZIKV infection, approved vaccines or antiviral drugs are still lacking. Consequently, the development of new effective anti-ZIKV agents is urgently needed. In this context, we investigated the antiviral potential of pyrazolone derivatives against ZIKV replication using in silico and in vitro methods. The four pyrazolone derivatives evaluated (1a, 1b, 1c, and 1d) inhibited over 50% of ZIKV replication with low cytotoxicity. Among them, compound 1b exhibited the most potent activity (EC50 = 4.3 μM) and the highest selectivity (SI = 342). Mechanism of action studies indicated that these compounds act at early stages of virus replication, and compound 1b can also directly inactivate ZIKV particles. Molecular docking studies suggested that these compounds can bind to and block the activity of ZIKV NS5 methyltransferase. Finally, pharmacokinetic and toxicological predictions have reinforced the safety and drug-like profiles of these derivatives. In conclusion, the pyrazolone scaffold proved to be valuable for anti-ZIKV drug development, and the derivatives studied deserve further investigation.展开更多
Although the Centers for Disease Control and Prevention (CDC) reports that brain abnormalities in infants with laboratory-confirmed Zika infection include microcephaly, disrupted brain growth, intracranial calcificati...Although the Centers for Disease Control and Prevention (CDC) reports that brain abnormalities in infants with laboratory-confirmed Zika infection include microcephaly, disrupted brain growth, intracranial calcifications, and abnormal eye findings—it is not known presently if the Zika virus itself causes any of these. In a recent 2016 review of Zika dealing with possible brain abnormalities appearing with Zika, Melo et al. mention that among the Flaviviruses, which Zika is, such brain insults and pathologic findings are practically unheard of. Melo et al. conclude that until more cases are diagnosed and more histopathological proofs are obtained, the possibility of other causes besides Zika cannot be ruled out. This paper considers just such other possible causes that have, to this point, escaped general notice. The Aedes aegypti and other Aedes species can transmit tiny viral-like, cell-wall-deficient mycobacterial forms, independent of viruses, yet prevalent in the very same Rhesus Monkey used in the original 1952 Zika communication—which spoke of “A filterable transmissible agent”. In addition, the universal fetal prenatal vaccination of Brazilian neonates is considered, strongly discouraged by The Royal Children’s Hospital in Melbourne, which forbids BCG vaccination of pregnant women and those immunosuppressed or already having tuberculosis (TB) or AIDS. And finally thought is focused on the prime candidate itself, towards explaining what an alternative cause for “Zika” might look like—an infectious agent with transmissible, filterable, viral-like forms. One which can be transmitted by the very same Aedes mosquitoes that carry Zika—one that is neurotrophic, and extremely prevalent in Brazil—and that can disrupt brain growth, cause microcephalus, cause a fever, is sexually transmissible, instigates Guillain-Barré syndrome and causes cranial calcifications—the Mycobacterium tuberculosis complex, which includes the Mycobacterium africanum prevalent, yet completely ignored, in the Rhesus monkeys used in the original Zika study.展开更多
Objective:To assess the knowledge on Zika virus(ZIKV) infection among healthcare providers(doctors) in Aceh province,Indonesia.Methods:A self-administered internet based survey was conducted from 3 May to 3 June 2016 ...Objective:To assess the knowledge on Zika virus(ZIKV) infection among healthcare providers(doctors) in Aceh province,Indonesia.Methods:A self-administered internet based survey was conducted from 3 May to 3 June 2016 among the members of doctor organizations in Aceh province.A set of validated,pre-tested questionnaire was used to measure knowledge regarding ZIKV infection and to collect a range of explanatory variables.A two-steps logistic regression analysis was employed to assess the association of participants' demographic,workplace characteristics and other explanatory variables with the knowledge.Results:A total of 442 participants included in the final analysis and 35.9% of them(159) had a good knowledge on ZIKV infection.Multivariate model revealed that type of occupation,type of workplace,availability of access to medical journals and experience made Zika disease as differential diagnose were associated with knowledge on ZIKV infection.In addition,three significant source of information regarding ZIKV were online media(60%),medical article or medical news(16.2%) and television(13.2%).Conclusion:The knowledge of the doctors in Aceh regarding ZIKV infection is relatively low.Doctors who have a good knowledge on ZIKV infection are more confident to established ZIKV disease as differential diagnosis in their clinical setting.Therefore,such program to increase healthcare providers' knowledge regarding ZIKV infection is needed to screen potential carriers of ZIKV infection.展开更多
Background:Latin America presently has the world’s highest burden of Zika virus,but there are unexplained differences in national rates of congenital malformations collectively referred to as Congenital Zika Syndrome...Background:Latin America presently has the world’s highest burden of Zika virus,but there are unexplained differences in national rates of congenital malformations collectively referred to as Congenital Zika Syndrome(CZS)in the region.While Zika virulence and case detection likely contribute to these differences,policy-related factors,including access to abortion,may play important roles.Our goal was to assess perspectives on,and access to,abortion in Latin America in the context of the Zika epidemic.Methods:We conducted a scoping review of peer-reviewed and gray literature published between January 2015 and December 2016,written in English,Spanish,Portuguese,or French.We searched PubMed,Scielo,and Google Scholar for literature on Zika and/or CZS and abortion,and used automated and manual review methods to synthesize the existing information.Results:36 publications met our inclusion criteria,the majority of which were qualitative.Publications were generally in favor of increased access to safe abortion as a policy-level response for mitigating the impact of CZS,but issues with implementation were cited as the main challenge.Aside from the reform of abortion regulation in Colombia,we did not find evidence that the Zika epidemic had triggered shifts in abortion policy in other countries.Conclusion:Abortion policy in the region remained largely unchanged following the Zika epidemic.Further empirical research on abortion access and differential rates of CZS across Latin American countries is required.展开更多
Objective: To identify immunological evidence of Zika virus transmission in Thailand. Methods: To undertake a preliminary serosurvey of possible exposure to Zika virus, 21 serum samples from cohort of acute undifferen...Objective: To identify immunological evidence of Zika virus transmission in Thailand. Methods: To undertake a preliminary serosurvey of possible exposure to Zika virus, 21 serum samples from cohort of acute undifferentiated fever patients were examined for immunoreactivity to Zika, Dengue, Japanese encephalitis and Chikungunya envelope antigens by Western blot analysis. Results: Twenty of the 21 serum samples showed immunoreactivity to at least one of the antigens, with seven samples showing immunoreactivity to all antigens. Of particular note, two serum samples showed immunoreactivity only to Zika envelope antigen, with no immunoreactivity to other envelope antigens. Conclusions: This study presents the first evidence of Zika virus transmission in Thailand, although as yet the relationship between transmission and possible cases of Zika fever in Thailand requires further investigation.展开更多
Zika virus infection is the present problematic arboviral disease. Classically, this disease cause febrile illness and can result in low platelet count. However, there are some new obervations on atypical clinical pre...Zika virus infection is the present problematic arboviral disease. Classically, this disease cause febrile illness and can result in low platelet count. However, there are some new obervations on atypical clinical presentations of Zika virus infection that can make the diagnosis more difficult. The afebrile, asymptomatic and non-thrombocytopenic Zika virus infection can be seen in clinical practice and can lead to missed or delayed diagnosis.展开更多
The risk of dengue virus transmission via blood transfusion is confirmed.As a similar virus,the risk for the case of Zika virus should be mentioned.Here,the authors calculated for the risk of Zika virus transmission v...The risk of dengue virus transmission via blood transfusion is confirmed.As a similar virus,the risk for the case of Zika virus should be mentioned.Here,the authors calculated for the risk of Zika virus transmission via blood transmission referring to the previous data on the risk in case of dengue virus.展开更多
基金This work is supported by the United Arab Emirates University UPAR(Grant No.G3458).
文摘Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.
基金supported by a research grant from the Ministry of Education,Culture,Research and Technology(KEMENDIKBUD RISTEK)number NKB-022/UN2.RST/HKP.05.00/2021 awarded to AB.
文摘Objective:To characterize the infection patterns and growth characteristics of the Zika virus(ZIKV)strain JMB-185 from Indonesia in various mammalian cell lines.Methods:ZIKV was grown in human(A549,HEK293,HepG2,Huh7,Jurkat,and THP-1)and non-human mammalian(RAW264.7,Vero,and Vero76)cell lines.Viral replication kinetics were measured using plaque assay,while intra-and extracellular viral RNA concentrations were assessed using RT-PCR.Flow cytometry was used to quantify the infected cells and cell viability was measured using an MTT assay.The ability of ZIKV to infect cell lines was visualized using a fluorescence immunostaining assay.Results:This ZIKV strain preferentially infected the lung,kidney,and liver cell lines A549,HEK293,Huh7,Vero,and Vero76,but not the immune cells Jurkat,RAW264.7,and THP-1.By contrast,the ZIKV showed no sign of infection in HepG2 cells,while maintaining viral titer over 3 days post-infection,with no infection recorded in immunostaining,no increase in viral RNA,and no indication of cell deterioration.Conclusions:The Indonesian ZIKV strain has a similar infection profile as other strains,except for its poor infectivity on HepG2 cells.Information on the growth characteristics of Indonesia ZIKV will help expand our understanding of the biology of ZIKV which will be useful for various applications including antiviral discovery.
文摘Objectives To identify the 5'untranslated region of Zika virus(ZIKV 5'UTR)RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site(IRES)located in ZIKV 5'UTR and virus production.Methods Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining,Subsequently,liquid chromatographytandem mass spectrometry(LC-MS/MS),bioinformatics analysis,and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR.Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production,respecitvely.Results tRSA RNA pull-down assay,LC-MS/MS,and Western blot analysis showed that polypyrimidine tractbinding protein(PTB)bound to the ZIKV 5'UTR.Furthermore,dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV(t=10.220,P<0.001),while PTB knockdown had the opposite effect(t=4.897,P<0.01).Additionally,virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer(t=6.400,P<0.01),whereas reducing PTB expression level weakened virus infectivity(t=5.055,P<0.01).Conclusion PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production.
文摘Zika virus (ZIKV), a mosquito-borne flavivirus, has been associated with benign infections for decades. However, it has become a public health concern due to its association with severe fetal and neurological complications. Although many efforts have been made to control ZIKV infection, approved vaccines or antiviral drugs are still lacking. Consequently, the development of new effective anti-ZIKV agents is urgently needed. In this context, we investigated the antiviral potential of pyrazolone derivatives against ZIKV replication using in silico and in vitro methods. The four pyrazolone derivatives evaluated (1a, 1b, 1c, and 1d) inhibited over 50% of ZIKV replication with low cytotoxicity. Among them, compound 1b exhibited the most potent activity (EC50 = 4.3 μM) and the highest selectivity (SI = 342). Mechanism of action studies indicated that these compounds act at early stages of virus replication, and compound 1b can also directly inactivate ZIKV particles. Molecular docking studies suggested that these compounds can bind to and block the activity of ZIKV NS5 methyltransferase. Finally, pharmacokinetic and toxicological predictions have reinforced the safety and drug-like profiles of these derivatives. In conclusion, the pyrazolone scaffold proved to be valuable for anti-ZIKV drug development, and the derivatives studied deserve further investigation.
文摘Although the Centers for Disease Control and Prevention (CDC) reports that brain abnormalities in infants with laboratory-confirmed Zika infection include microcephaly, disrupted brain growth, intracranial calcifications, and abnormal eye findings—it is not known presently if the Zika virus itself causes any of these. In a recent 2016 review of Zika dealing with possible brain abnormalities appearing with Zika, Melo et al. mention that among the Flaviviruses, which Zika is, such brain insults and pathologic findings are practically unheard of. Melo et al. conclude that until more cases are diagnosed and more histopathological proofs are obtained, the possibility of other causes besides Zika cannot be ruled out. This paper considers just such other possible causes that have, to this point, escaped general notice. The Aedes aegypti and other Aedes species can transmit tiny viral-like, cell-wall-deficient mycobacterial forms, independent of viruses, yet prevalent in the very same Rhesus Monkey used in the original 1952 Zika communication—which spoke of “A filterable transmissible agent”. In addition, the universal fetal prenatal vaccination of Brazilian neonates is considered, strongly discouraged by The Royal Children’s Hospital in Melbourne, which forbids BCG vaccination of pregnant women and those immunosuppressed or already having tuberculosis (TB) or AIDS. And finally thought is focused on the prime candidate itself, towards explaining what an alternative cause for “Zika” might look like—an infectious agent with transmissible, filterable, viral-like forms. One which can be transmitted by the very same Aedes mosquitoes that carry Zika—one that is neurotrophic, and extremely prevalent in Brazil—and that can disrupt brain growth, cause microcephalus, cause a fever, is sexually transmissible, instigates Guillain-Barré syndrome and causes cranial calcifications—the Mycobacterium tuberculosis complex, which includes the Mycobacterium africanum prevalent, yet completely ignored, in the Rhesus monkeys used in the original Zika study.
文摘Objective:To assess the knowledge on Zika virus(ZIKV) infection among healthcare providers(doctors) in Aceh province,Indonesia.Methods:A self-administered internet based survey was conducted from 3 May to 3 June 2016 among the members of doctor organizations in Aceh province.A set of validated,pre-tested questionnaire was used to measure knowledge regarding ZIKV infection and to collect a range of explanatory variables.A two-steps logistic regression analysis was employed to assess the association of participants' demographic,workplace characteristics and other explanatory variables with the knowledge.Results:A total of 442 participants included in the final analysis and 35.9% of them(159) had a good knowledge on ZIKV infection.Multivariate model revealed that type of occupation,type of workplace,availability of access to medical journals and experience made Zika disease as differential diagnose were associated with knowledge on ZIKV infection.In addition,three significant source of information regarding ZIKV were online media(60%),medical article or medical news(16.2%) and television(13.2%).Conclusion:The knowledge of the doctors in Aceh regarding ZIKV infection is relatively low.Doctors who have a good knowledge on ZIKV infection are more confident to established ZIKV disease as differential diagnosis in their clinical setting.Therefore,such program to increase healthcare providers' knowledge regarding ZIKV infection is needed to screen potential carriers of ZIKV infection.
文摘Background:Latin America presently has the world’s highest burden of Zika virus,but there are unexplained differences in national rates of congenital malformations collectively referred to as Congenital Zika Syndrome(CZS)in the region.While Zika virulence and case detection likely contribute to these differences,policy-related factors,including access to abortion,may play important roles.Our goal was to assess perspectives on,and access to,abortion in Latin America in the context of the Zika epidemic.Methods:We conducted a scoping review of peer-reviewed and gray literature published between January 2015 and December 2016,written in English,Spanish,Portuguese,or French.We searched PubMed,Scielo,and Google Scholar for literature on Zika and/or CZS and abortion,and used automated and manual review methods to synthesize the existing information.Results:36 publications met our inclusion criteria,the majority of which were qualitative.Publications were generally in favor of increased access to safe abortion as a policy-level response for mitigating the impact of CZS,but issues with implementation were cited as the main challenge.Aside from the reform of abortion regulation in Colombia,we did not find evidence that the Zika epidemic had triggered shifts in abortion policy in other countries.Conclusion:Abortion policy in the region remained largely unchanged following the Zika epidemic.Further empirical research on abortion access and differential rates of CZS across Latin American countries is required.
基金supported by Mahidol University and the Thailand Research Fund(RTA5780009 and IRG5780009)supported by a Mahidol University Post-Doctoral Fellowship
文摘Objective: To identify immunological evidence of Zika virus transmission in Thailand. Methods: To undertake a preliminary serosurvey of possible exposure to Zika virus, 21 serum samples from cohort of acute undifferentiated fever patients were examined for immunoreactivity to Zika, Dengue, Japanese encephalitis and Chikungunya envelope antigens by Western blot analysis. Results: Twenty of the 21 serum samples showed immunoreactivity to at least one of the antigens, with seven samples showing immunoreactivity to all antigens. Of particular note, two serum samples showed immunoreactivity only to Zika envelope antigen, with no immunoreactivity to other envelope antigens. Conclusions: This study presents the first evidence of Zika virus transmission in Thailand, although as yet the relationship between transmission and possible cases of Zika fever in Thailand requires further investigation.
文摘Zika virus infection is the present problematic arboviral disease. Classically, this disease cause febrile illness and can result in low platelet count. However, there are some new obervations on atypical clinical presentations of Zika virus infection that can make the diagnosis more difficult. The afebrile, asymptomatic and non-thrombocytopenic Zika virus infection can be seen in clinical practice and can lead to missed or delayed diagnosis.
文摘The risk of dengue virus transmission via blood transfusion is confirmed.As a similar virus,the risk for the case of Zika virus should be mentioned.Here,the authors calculated for the risk of Zika virus transmission via blood transmission referring to the previous data on the risk in case of dengue virus.