Modification of the Untranslated Regions of Human Enterovirus 71 Impairs Growth in a Cell-Specific Manner

Kok, Chee Choy; Phuektes, Patchara; Bek, Emily J.; McMinn, Peter C.

doi:10.1128/jvi.00069-11

Cited by 25 publications

(29 citation statements)

References 42 publications

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“…Furthermore, after amplification of infectious clones harboring EV71 subgenogroup B3 in SH-SY5Y and RD cell lines, VP1 94 was recently identified and is postulated to be important for cell-type adaptation [36]. Taken together, the region surrounding the VP1 L97R mutation identified in this study likely plays an important role in cell-type adaptation and potentially neurotropism, independent of the EV71 genogroup.…”

Section: Discussionmentioning

confidence: 56%

Identification of Site-Specific Adaptations Conferring Increased Neural Cell Tropism during Human Enterovirus 71 Infection

et al. 2012

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Enterovirus 71 (EV71) is one of the most virulent enteroviruses, but the specific molecular features that enhance its ability to disseminate in humans remain unknown. We analyzed the genomic features of EV71 in an immunocompromised host with disseminated disease according to the different sites of infection. Comparison of five full-length genomes sequenced directly from respiratory, gastrointestinal, nervous system, and blood specimens revealed three nucleotide changes that occurred within a five-day period: a non-conservative amino acid change in VP1 located within the BC loop (L97R), a region considered as an immunogenic site and possibly important in poliovirus host adaptation; a conservative amino acid substitution in protein 2B (A38V); and a silent mutation in protein 3D (L175). Infectious clones were constructed using both BrCr (lineage A) and the clinical strain (lineage C) backgrounds containing either one or both non-synonymous mutations. In vitro cell tropism and competition assays revealed that the VP1 97 Leu to Arg substitution within the BC loop conferred a replicative advantage in SH-SY5Y cells of neuroblastoma origin. Interestingly, this mutation was frequently associated in vitro with a second non-conservative mutation (E167G or E167A) in the VP1 EF loop in neuroblastoma cells. Comparative models of these EV71 VP1 variants were built to determine how the substitutions might affect VP1 structure and/or interactions with host cells and suggest that, while no significant structural changes were observed, the substitutions may alter interactions with host cell receptors. Taken together, our results show that the VP1 BC loop region of EV71 plays a critical role in cell tropism independent of EV71 lineage and, thus, may have contributed to dissemination and neurotropism in the immunocompromised patient.

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Section: Discussionmentioning

confidence: 56%

Identification of Site-Specific Adaptations Conferring Increased Neural Cell Tropism during Human Enterovirus 71 Infection

et al. 2012

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“…The nascent positive-strand RNA is encapsidated. Viral particles are released from infected cells (10).…”

mentioning

confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 M and a 50% cytotoxic concentration of 119.97 M. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment.

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“…Replacement of the PV internal ribosome entry site (IRES), with that of a non-neurotropic human rhinovirus (HRV), was found to stably attenuate PV in animal models [149,150] . In HEV71, it was shown that deletion of stem-loop domain Z within the 3'-untranslated region attenuates the growth of a HEV71-HRV2-IRES chimera in neuroblastoma cells [151] . Another strategy employed to generate stably attenuated vaccine strains is to increase the replication fidelity of the 3D polymerase.…”

Section: Live-attenuated Vaccinementioning

confidence: 99%

Therapeutic and prevention strategies against human enterovirus 71 infection

Kok

2015

WJV

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Human enterovirus 71 (HEV71) is the cause of hand, foot and mouth disease and associated neurological complications in children under five years of age. There has been an increase in HEV71 epidemic activity throughout the Asia-Pacific region in the past decade, and it is predicted to replace poliovirus as the extant neurotropic enterovirus of highest global public health significance. To date there is no effective antiviral treatment and no vaccine is available to prevent HEV71 infection. The increase in prevalence, virulence and geographic spread of HEV71 infection over the past decade provides increasing incentive for the development of new therapeutic and prevention strategies against this emerging viral infection. The current review focuses on the potential, advantages and disadvantages of these strategies. Since the explosion of outbreaks leading to large epidemics in China, research in natural therapeutic products has identified several groups of compounds with anti-HEV71 activities. Concurrently, the search for effective synthetic antivirals has produced promising results. Other therapeutic strategies including immunotherapy and the use of oligonucleotides have also been explored. A sound prevention strategy is crucial in order to control the spread of HEV71. To this end the ultimate goal is the rapid development, regulatory approval and widespread implementation of a safe and effective vaccine. The various forms of HEV71 vaccine designs are highlighted in this review. Given the rapid progress of research in this area, eradication of the virus is likely to be achieved. Core tip: This review focuses on therapeutic and prevention strategies for the control of human enterovirus 71 infection. Therapeutic strategies highlighted include natural products, synthetic antivirals, immunotherapy, and the use of olignucleotides. Prevention strategies such as surveillance, physical prevention, and vaccine development form the second part of the review.Kok CC. Therapeutic and prevention strategies against human enterovirus 71 infection. World J Virol 2015; 4(2): 78-95 Available from:

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Modification of the Untranslated Regions of Human Enterovirus 71 Impairs Growth in a Cell-Specific Manner

Cited by 25 publications

References 42 publications

Identification of Site-Specific Adaptations Conferring Increased Neural Cell Tropism during Human Enterovirus 71 Infection

Identification of Site-Specific Adaptations Conferring Increased Neural Cell Tropism during Human Enterovirus 71 Infection

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Therapeutic and prevention strategies against human enterovirus 71 infection

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