Enterovirus 71 (EV71) is an important human pathogen which may cause severe neurological complications and death in children. The virus caused several outbreaks in the Asia-Pacific region during the past two decades and has been considered a significant public health problem in the post-poliovirus eradication era. Unlike poliovirus, there is no effective vaccine or approved antivirals against EV71. To explore anti-EV71 agents therefore is of vital importance. Several strategies have been employed to develop antivirals based on the molecular characteristics of the virus. Among these, some small molecules that were developed against human rhinoviruses and poliovirus are under evaluation. In this review, we discuss the recent development of such small molecules against EV71, known drug resistance and possible solutions to it, and animal models for evaluating the efficacy of these antivirals. Although further investigation is required for clinical applications of the existing candidates, the molecular mechanisms revealed for the inhibition of EV71 replication can be used for designing new molecules against this virus in the future.
Enterovirus 71 (EV71) is an etiology for a number of diseases in humans. Traditional Chinese herbs have been reported to be effective for treating EV71 infection. However, there is no report about the antiviral effects of CHA against EV71. In this study, plaque reduction assay demonstrated that the inhibitory concentration 50% (IC50) of CHA on EV71 replication is 6.3 µg/ml. When both CHA (20 µg/ml) and EV71 were added, or added post-infection at different time points, CHA was able to effectively inhibit EV71 replication between 0 and 10 h. In addition, CHA inhibited EV71 2A transcription and translation in EV71-infected RD cells, but did not affect VP1, 3C, and 3D expression. Furthermore, CHA inhibited secretions of IL-6, TNF-α, IFN-γ and MCP-1 in EV71-infected RD cells. Altogether, these results revealed that CHA may have antiviral properties for treating EV71 infection.
Enterovirus 71 (EV71) is a group of viruses that belongs to the Picornaviridae family, which also includes viruses such as polioviruses. EV71, together with coxsackieviruses, is widely known for its association with Hand Foot Mouth Disease (HFMD), which generally affects children age five and below. Besides HFMD, EV71 can also trigger more severe and life-threatening neurological conditions such as encephalitis. Considering the lack of a vaccine and antiviral drug against EV71, together with the increasing spread of these viruses, the development of such drugs and vaccines becomes the top priority in protecting our younger generations. This article, hence, reviews some of the recent progress in the formulations of anti-therapeutics and vaccine generation for EV71, covering (i) inactivated vaccines; (ii) baculovirus-expressed vaccines against EV71; (iii) human intravenous immunoglobulin (IVIg) treatment; and (iv) the use of monoclonal antibody therapy as a prevention and treatment for EV71 infections.
In 1988, the World Health Assembly resolved to eradicate poliomyelitis. Wild poliovirus (WPV) transmission persists in only two countries (Afghanistan and Pakistan) after the removal of Nigeria from the list of countries with endemic polio in September 2015.* Indigenous WPV type 2 has not been detected since 1999 and was declared eradicated by the Global Commission for the Certification of Poliomyelitis Eradication in September 2015.(†) Since November 2012, when the last case of WPV type 3 was detected in Nigeria, WPV type 1 has been the sole circulating type of WPV (1). This report summarizes global progress toward polio eradication during 2015-2016 and updates previous reports (2). In 2015, 74 WPV cases were reported in two countries (Afghanistan and Pakistan), a decrease of 79% from the 359 WPV cases reported in 2014 in nine countries; 12 WPV cases have been reported in 2016 (to date), compared with 23 during the same period in 2015 (3). Paralytic polio caused by circulating vaccine-derived poliovirus (cVDPV) remains a risk in areas with low oral poliovirus vaccine (OPV) coverage. Seven countries, including Pakistan, reported 32 cVDPV cases in 2015 (4). In four of these countries, ≥6 months have passed since the most recent case or isolate. One country (Laos) with VDPV transmission in 2015 has reported three additional cVDPV cases in 2016 to date. Encouraging progress toward polio eradication has been made over the last year; however, interruption of WPV transmission will require focus on reaching and vaccinating every missed child through high quality supplementary immunization activities (SIAs) and cross-border coordination between Afghanistan and Pakistan (5,6).
Background The last case of infection with wild-type poliovirus indigenous to China was reported in 1994, and China was certified as a poliomyelitis-free region in 2000. In 2011, an outbreak of infection with imported wild-type poliovirus occurred in the province of Xinjiang. Methods We conducted an investigation to guide the response to the outbreak, performed sequence analysis of the poliovirus type 1 capsid protein VP1 to determine the source, and carried out serologic and coverage surveys to assess the risk of viral propagation. Surveillance for acute flaccid paralysis was intensified to enhance case ascertainment. Results Between July 3 and October 9, 2011, investigators identified 21 cases of infection with wild-type poliovirus and 23 clinically compatible cases in southern Xinjiang. Wild-type poliovirus type 1 was isolated from 14 of 673 contacts of patients with acute flaccid paralysis (2.1%) and from 13 of 491 healthy persons who were not in contact with affected persons (2.6%). Sequence analysis implicated an imported wild-type poliovirus that originated in Pakistan as the cause of the outbreak. A public health emergency was declared in Xinjiang after the outbreak was confirmed. Surveillance for acute flaccid paralysis was enhanced, with daily reporting from all public and private hospitals. Five rounds of vaccination with live, attenuated oral poliovirus vaccine (OPV) were conducted among children and adults, and 43 million doses of OPV were administered. Trivalent OPV was used in three rounds, and monovalent OPV type 1 was used in two rounds. The outbreak was stopped 1.5 months after laboratory confirmation of the index case. Conclusions The 2011 outbreak in China showed that poliomyelitis-free countries remain at risk for outbreaks while the poliovirus circulates anywhere in the world. Global eradication of poliomyelitis will benefit all countries, even those that are currently free of poliomyelitis.
- Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology
- Published over 5 years ago
BACKGROUND: Human enterovirus 71 (HEV71) is a common cause of severe outbreaks of hand-foot- and mouth disease, aseptic meningitis and encephalitis in Asian populations but has not caused such epidemics in all populations. OBJECTIVES: To analyze the frequency of HEV71 in the background childhood population in Finland by screening in stool and serum samples and by measuring neutralizing antibodies against HEV71 in serum and to compare the genetic relationship of virus strains detected in asymptomatic children and those causing severe illness in Finland to the strains found in other countries. STUDY DESIGN: 4185 stool samples and 5686 serum samples were collected and clinical symptoms recorded from children who were observed from birth. Additional stool samples were available from four children hospitalized due to EV71 infection. Samples were screened for the presence of RNA of human enteroviruses using RT-PCR and HEV71 amplicons were identified by sequencing. Phylogenetic analyses were carried out to study genetic relationships between different virus strains. Neutralizing antibodies against HEV71 were screened from 522 children. RESULTS: A total of 0.3% of stool samples and two serum samples from healthy children were positive for HEV71 genome. 1.6% of the children had neutralizing antibodies against HEV71. Most infections were asymptomatic or mild in contrast to the clear symptoms in the children hospitalized due to HEV71. All viruses were C strains. CONCLUSIONS: HEV71 is circulating in Finland but it is rare. No clear difference was seen between strains circulating in the Finnish background population and those found in hospitalized patients or those causing severe outbreaks worldwide.
Human enteroviruses (HEVs) are endemic worldwide and among the most common viruses infecting humans. Nevertheless, there is very limited data on the circulation and genetic diversity of HEVs in developing countries, and sub-Saharan Africa in particular.We investigated the circulation and genetic diversity of HEVs among 436 healthy children in a limited area of the far North region of Cameroon in 2008 and 2009. We also characterized the genetic biodiversity of 146 non-polio enterovirus (NPEV) isolates obtained throughout the year 2008 from the stool specimens of patients with acute flaccid paralysis (AFP) in Cameroon, Chad and Gabon.We found a high rate of NPEV infections (36.9%) among healthy children in the far North region of Cameroon. Overall 45 different HEV types were found among healthy children and AFP patients. Interestingly, this study uncovered a high rate of HEVs of species C (HEV-C) among all typed NPEVs: 63.1% (94/149) and 39.5% (49/124) in healthy children and AFP cases, respectively. Besides extensive circulation, the most prevalent HEV-C type, coxsackievirus A-13, featured a tremendous intratypic diversity. African specific HEV lineages were discovered, including HEV-C lineages and the recently reported EV-A71 “genogroup E”.Virtually all pathogenic circulating vaccine-derived polioviruses (cVDPVs) that have been fully characterized were recombinants between oral poliovaccine (OPV) strains and co-circulating HEV-C. The extensive circulation of diverse HEV-C types and lineages in countries where OPV is massively used constitutes a major viral factor that could promote the emergence of recombinant cVDPVs in the Central African sub-region.
Enterovirus 71 (EV71) is a member of the Picornaviridae family and one of the main causative agents of hand, foot, and mouth disease (HFMD). Currently, EV71 infection is prevalent in the Asia-Pacific regions where it affects millions of children under the age of five, causing significant morbidity and mortality. No specific vaccine or antiviral drugs are available for EV71. The development of murine monoclonal antibodies (mAbs) with potent neutralization effects on EV71 is described. Mab-secreting hybridomas were generated from mice immunized with EV71 recombinant virus-like particles. Three IgG1 mAbs, D5, H7, and C4, capable of binding to and neutralizing EV71, were identified. In ELISA and Western blot assays, these mAbs reacted with recombinant VP1 protein, but not with VP0. They also detected cells infected with EV71 by immunofluorescent staining. In addition, these three mAbs had potent EV71 neutralization capacity, with 95% inhibitory concentrations of 0.3125, 0.3125, and 1.25μg/ml for D5, H7, and C4, respectively. The presented data demonstrate that the anti-EV71 mAbs are not only promising candidates for development into humanized mAb for treatment but also useful reagents for development of diagnostic tests.
The Picornaviridae are a large family of small, spherical RNA viruses that includes numerous pathogens. The picornavirus structural proteins VP0, VP1, and VP3 are believed to first form protomers, which then form 14S particles and subsequently assemble to form empty and RNA-filled particles. 14S particles have long been presumed to be pentamers. However, the structure of the 14S particles, their mechanism of assembly, and the role of empty particles during infection are all unknown. We established an in vitro assembly system for bovine enterovirus (BEV) by using purified baculovirus-expressed proteins. By Rayleigh scattering, we determined that 14S particles are 488 kDa, confirming they are pentamers. Image reconstructions based on negative-stain electron microscopy showed that 14S particles have 5-fold symmetry, and their structures correlate extremely well with the corresponding pentamer from crystal structures of mature BEV. Purified 14S particles readily assemble in response to increasing ionic strength or temperature to form 5.8-MDa 12-pentamer particles, indistinguishable from native empty particles. Surprisingly, empty particles were sufficiently stable that, under physiological conditions, dissociation is unlikely to be a biologically relevant reaction. This suggests that empty particles are not a storage form of 14S particles, at least for bovine enterovirus, but are either a dead-end product or direct precursor into which viral RNA is packaged by as-yet-unidentified machinery.
BACKGROUND: Enterovirus 71 (EV71) is a major causative agent of hand-foot-and-mouth disease (HFMD), and infection of EV71 to central nerve system (CNS) may result in a high mortality in children less than 2 years old. Although there are two highly glycosylated membrane proteins, SCARB2 and PSGL-1, which have been identified as the cellular and functional receptors of EV71, the role of glycosylation in EV71 infection is still unclear. RESULTS: We demonstrated that the attachment of EV71 to RD and SK-N-SH cells was diminished after the removal of cell surface sialic acids by neuraminidase. Sialic acid specific lectins, MAA and SNA, could compete with EV71 and restrained the binding of EV71 significantly. Preincubation of RD cells with fetuin also reduced the binding of EV71. In addition, we found that SCARB2 was a sialylated glycoprotein and interaction between SCARB2 and EV71 was retarded after desialylation. CONCLUSIONS: In this study, we demonstrated that cell surface sialic acids assist in the attachment of EV71 to host cells. Cell surface sialylation should be a key regulator that facilitates the binding and infection of EV71 to RD and SK-N-SH cells.