The life cycle of non-polio enteroviruses and how to target it

Nature Reviews Microbiology

Volumn 16, Issue 6, 2018, Pages 368-381

  Baggen, Jim ^a   Thibaut, Hendrik Jan ^a   Strating, Jeroen R P M ^a   Van Kuppeveld, Frank J M ^a  

^a UTRECHT UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; ENTEROVIRUS VACCINE; HOST FACTOR; PHOSPHOLIPASE A2; PHOSPHOLIPASE A2 GROUP XVI; UNCLASSIFIED DRUG; VIRULENCE FACTOR; VIRUS RECEPTOR; VIRUS VACCINE;

ANTIVIRAL ACTIVITY; ANTIVIRAL THERAPY; CHANNEL GATING; DRUG TARGETING; ENTEROVIRUS; ENTEROVIRUS INFECTION; HUMAN; LIFE CYCLE; NON POLIO ENTEROVIRUS; NON POLIO ENTEROVIRUS INFECTION; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; REVIEW; VACCINATION; VIRAL PHENOMENA AND FUNCTIONS; VIRION; VIROGENESIS; VIRUS ASSEMBLY; VIRUS ENTRY; VIRUS GENOME; VIRUS MORPHOLOGY; VIRUS RELEASE; VIRUS REPLICATION; VIRUS UNCOATING; VIRUS VIRULENCE; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; GLOBAL HEALTH; PHYSIOLOGY; VIROLOGY;

ANIMALS; ANTIVIRAL AGENTS; ENTEROVIRUS; ENTEROVIRUS INFECTIONS; GENE EXPRESSION REGULATION, VIRAL; GLOBAL HEALTH; HUMANS; VIRUS REPLICATION;

EID: 85045089082     PISSN: 17401526     EISSN: 17401534     Source Type: Journal    
DOI: 10.1038/s41579-018-0005-4     Document Type: Review

References (164)

1. Racaniello, V. R. & Baltimore, D. Molecular cloning of poliovirus cDNA and determination of the complete nucleotide sequence of the viral genome. Proc. Natl Acad. Sci. USA 78, 4887-4891 (1981).
2. Racaniello, V. & Baltimore, D. Cloned poliovirus complementary DNA is infectious in mammalian cells. Science 214, 916-919 (1981).
3. Hogle, J., Chow, M. & Filman, D. Three-dimensional structure of poliovirus at 2. 9 A resolution. Science 229, 1358-1365 (1985).
4. Rossmann, M. G. et al. Structure of a human common cold virus and functional relationship to other picornaviruses. Nature 317, 145-153 (1985).
5. Pons-Salort, M., Parker, E. P. K. & Grassly, N. C. The epidemiology of non-polio enteroviruses. Curr. Opin. Infect. Dis. 28, 479-487 (2015).
6. Hober, D. & Sauter, P. Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host. Nat. Rev. Endocrinol. 6, 279-289 (2010).
7. Thibaut, H. J. et al. Toward antiviral therapy/ prophylaxis for rhinovirus-induced exacerbations of chronic obstructive pulmonary disease: challenges, opportunities, and strategies. Rev. Med. Virol. 26, 21-33 (2016).
8. Ooi, M. H., Wong, S. C., Lewthwaite, P., Cardosa, M. J. & Solomon, T. Clinical features, diagnosis, and management of enterovirus 71. Lancet Neurol. 9, 1097-1105 (2010).
9. Yi, E.-J., Shin, Y.-J., Kim, J.-H., Kim, T.-G. & Chang, S.-Y. Enterovirus 71 infection and vaccines. Clin. Exp. Vaccine Res. 6, 4-14 (2017).
10. Messacar, K. et al. A cluster of acute flaccid paralysis and cranial nerve dysfunction temporally associated with an outbreak of enterovirus D68 in children in CO, USA. Lancet 385, 1662-1671 (2015).
11. Holm-Hansen, C. C., Midgley, S. E. & Fischer, T. K. Global emergence of enterovirus D68: a systematic review. Lancet Infect. Dis. 16, e64-e75 (2016).
12. van der Schaar, H. M., Dorobantu, C. M., Albulescu, L., Strating, J. R. P. M. & van Kuppeveld, F. J. M. Fat(al) attraction: picornaviruses usurp lipid transfer at membrane contact sites to create replication organelles. Trends Microbiol. 24, 535-546 (2016).
13. L loyd, R. E. Enterovirus control of translation and RNA granule stress responses. Viruses 8, 1-16 (2016).
14. L loyd, R. E. Nuclear proteins hijacked by mammalian cytoplasmic plus strand RNA viruses. Virology 479-480, 457-474 (2015).
15. Feng, Q., Langereis, M. A. & van Kuppeveld, F. J. M. Induction and suppression of innate antiviral responses by picornaviruses. Cytokine Growth Factor Rev. 25, 577-585 (2014).
16. Harris, K. G. & Coyne, C. B. Death waits for no man - does it wait for a virus? How enteroviruses induce and control cell death. Cytokine Growth Factor Rev. 25, 587-596 (2014).
17. L ai, J. K. F., Sam, I.-C. & Chan, Y. F. The autophagic machinery in Enterovirus infection. Viruses 449, 35-44 (2016).
18. Kew, O. M., Sutter, R. W., de Gourville, E. M., Dowdle, W. R. & Pallansch, M. A. Vaccine-derived polioviruses and the endgame strategy for global polio eradication. Annu. Rev. Microbiol. 59, 587-635 (2005).
19. Benschop, K. S. M., van der Avoort, H. G. A. M., Duizer, E. & Koopmans, M. P. G. Antivirals against enteroviruses: a critical review from a public-health perspective. Antivir. Ther. 20, 121-130 (2015).
20. Rossmann, M. G., He, Y. & Kuhn, R. J. Picornavirusreceptor interactions. Trends Microbiol. 10, 324-331 (2002).
21. L iu, Y. et al. Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma. Proc. Natl Acad. Sci. USA 113, 8997-9002 (2016).
22. L iu, Y. et al. Structure and inhibition of EV-D68, a virus that causes respiratory illness in children. Science 347, 71-74 (2015).
23. Zhu, L. et al. Structure of human Aichi virus and implications for receptor binding. Nat. Microbiol. 1, 16150 (2016).
24. Wang, X. et al. Hepatitis A virus and the origins of picornaviruses. Nature 517, 85-88 (2014).
25. Zhu, L. et al. Structure of Ljungan virus provides insight into genome packaging of this picornavirus. Nat. Commun. 6, 8316 (2015).
26. Roedig, P. et al. High-speed fixed-target serial virus crystallography. Nat. Methods 14, 805-810 (2017).
27. Thibaut, H. J., De Palma, A. M. & Neyts, J. Combating enterovirus replication: state-of-the-art on antiviral research. Biochem. Pharmacol. 83, 185-192 (2012).
28. Mendelsohn, C. L., Wimmer, E. & Racaniello, V. R. Cellular receptor for poliovirus: molecular cloning, nucleotide sequence, and expression of a new member of the immunoglobulin superfamily. Cell 56, 855-865 (1989).
29. Greve, J. M. et al. The major human rhinovirus receptor is ICAM-1. Cell 56, 839-847 (1989).
30. L iu, Y. et al. Sialic acid-dependent cell entry of human enterovirus D68. Nat. Commun. 6, 8865 (2015).
31. Wei, W. et al. ICAM-5/telencephalin is a functional entry receptor for enterovirus D68. Cell Host Microbe 20, 631-641 (2016).
32. Coyne, C. B. & Bergelson, J. M. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119-131 (2006).
33. Baggen, J. et al. A role of enhanced receptor engagement in the evolution of a pandemic acute haemorrhagic conjunctivitis virus. Proc. Natl Acad. Sci. USA 115, 397-402 (2018).
34. Yamayoshi, S. et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat. Med. 15, 798-801 (2009).
35. Nishimura, Y. et al. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat. Med. 15, 794-797 (2009).
36. Yamayoshi, S., Ohka, S., Fujii, K. & Koike, S. Functional comparison of SCARB2 and PSGL1 as receptors for enterovirus 71. J. Virol. 87, 3335-3347 (2013).
37. L ei, X., Cui, S., Zhao, Z. & Wang, J. Etiology, pathogenesis, antivirals and vaccines of hand, foot, and mouth disease. Natl Sci. Rev. 2, 268-284 (2015).
38. Jiao, X. Y., Guo, L., Huang, D. Y., Chang, X. L. & Qiu, Q. C. Distribution of EV71 receptors SCARB2 and PSGL-1 in human tissues. Virus Res. 190, 40-52 (2014).
39. Fujii, K. et al. Transgenic mouse model for the study of enterovirus 71 neuropathogenesis. Proc. Natl Acad. Sci. USA 110, 14753-14758 (2013).
40. L amson, D. et al. MassTag polymerase chain reaction detection of respiratory pathogens, including a new rhinovirus genotype, that caused influenza like illness in New York state during 2004-2005. J. Infect. Dis. 194, 1398-1402 (2006).
41. Bochkov, Y. A. et al. Molecular modeling, organ culture and reverse genetics for a newly identified human rhinovirus C. Nat. Med. 17, 627-632 (2011).
42. Bochkov, Y. A. et al. Cadherin-related family member 3, a childhood asthma susceptibility gene product, mediates rhinovirus C binding and replication. Proc. Natl Acad. Sci. USA 112, 5485-5490 (2015).
43. Griggs, T. F. et al. Rhinovirus C targets ciliated airway epithelial cells. Respir. Res. 18, 84 (2017).
44. Bønnelykke, K. et al. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations. Nat. Genet. 46, 51-55 (2014).
45. Turner, R. B. et al. Efficacy of tremacamra, a soluble intercellular adhesion molecule 1, for experimental rhinovirus infection. JAMA 281, 1797-1804 (1999).
46. Kuo, R. L. & Shih, S. R. Strategies to develop antivirals against enterovirus 71. Virol. J. 10, 1 (2013).
47. Belnap, D. M. et al. Molecular tectonic model of virus structural transitions: the putative cell entry states of poliovirus. J. Virol. 74, 1342-1354 (2000).
48. L i, Q., Yafal, A. G., Lee, Y. M., Hogle, J. & Chow, M. Poliovirus neutralization by antibodies to internal epitopes of VP4 and VP1 results from reversible exposure of these sequences at physiological temperature. J. Virol. 68, 3965-3970 (1994).
49. Fricks, C. E. & Hogle, J. M. Cell-induced conformational change in poliovirus: externalization of the amino terminus of VP1 is responsible for liposome binding. J. Virol. 64, 1934-1945 (1990).
50. Crowell, R. L. & Philipson, L. Specific alterations of coxsackievirus B3 eluted from HeLa cells. J. Virol. 8, 509-515 (1971).
51. Wang, X. et al. A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71. Nat. Struct. Mol. Biol. 19, 424-429 (2012).
52. Prchla, E., Kuechler, E., Blaas, D. & Fuchs, R. Uncoating of human rhinovirus serotype 2 from late endosomes. J. Virol. 68, 3713-3723 (1994).
53. Hussain, K. M., Leong, K. L. J., Ng, M. M.-L. & Chu, J. J. H. The essential role of clathrin-mediated endocytosis in the infectious entry of human enterovirus 71. J. Biol. Chem. 286, 309-321 (2011).
54. Tosteson, M. T. & Chow, M. Characterization of the ion channels formed by poliovirus in planar lipid membranes. J. Virol. 71, 507-511 (1997).
55. Danthi, P., Tosteson, M., Li, Q.-H. & Chow, M. Genome delivery and ion channel properties are altered in VP4 mutants of poliovirus. J. Virol. 77, 5266-5274 (2003).
56. Davis, M. P. et al. Recombinant VP4 of human rhinovirus induces permeability in model membranes. J. Virol. 82, 4169-4174 (2008).
57. Panjwani, A. et al. Capsid protein VP4 of human rhinovirus induces membrane permeability by the formation of a size-selective multimeric pore. PLoS Pathog. 10, e1004294 (2014).
58. Strauss, M., Levy, H. C., Bostina, M., Filman, D. J. & Hogle, J. M. RNA transfer from poliovirus 135 S particles across membranes is mediated by long umbilical connectors. J. Virol. 87, 3903-3914 (2013).
59. Groppelli, E. et al. Picornavirus RNA is protected from clevage by ribonucleases during virion uncoating and transfer across cellular and model membranes. PLoS Pathog. 13, e1006197 (2017).
60. Harutyunyan, S. et al. Viral uncoating is directional: exit of the genomic RNA in a common cold virus starts with the poly-(A) tail at the 3?-end. PLoS Pathog. 9, e1003270 (2013).
61. Hadfield, A. T. et al. The refined structure of human rhinovirus 16 at 2. 15 A resolution: implications for the viral life cycle. Structure 5, 427-441 (1997).
62. L evy, H. C., Bostina, M., Filman, D. J. & Hogle, J. M. Catching a virus in the act of RNA release: a novel poliovirus uncoating intermediate characterized by cryo-electron microscopy. J. Virol. 84, 4426-4441 (2010).
63. Ren, J. et al. Picornavirus uncoating intermediate captured in atomic detail. Nat. Commun. 4, 1929 (2013).
64. Bostina, M., Levy, H., Filman, D. J. & Hogle, J. M. Poliovirus RNA is released from the capsid near a twofold symmetry axis. J. Virol. 85, 776-783 (2011).
65. L ee, H. et al. The novel asymmetric entry intermediate of a picornavirus captured with nanodiscs. Sci. Adv. 2, e1501929 (2016).
66. Brandenburg, B. et al. Imaging poliovirus entry in live cells. PLoS Biol. 5, 1543-1555 (2007).
67. Strauss, M., Schotte, L., Karunatilaka, K. S., Filman, D. J. & Hogle, J. M. Cryo-electron microscopy structures of expanded poliovirus with VHHs sample the conformational repertoire of the expanded state. J. Virol. 91, 1-22 (2017).
68. Staring, J. et al. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature 541, 412-416 (2017).
69. Zádori, Z. et al. A viral phospholipase A2 is required for parvovirus infectivity. Dev. Cell 1, 291-302 (2001).
70. L ozano, G. & Martínez-Salas, E. Structural insights into viral IRES-dependent translation mechanisms. Curr. Opin. Virol. 12, 113-120 (2015).
71. L ee, K. M., Chen, C. J. & Shih, S. R. Regulation mechanisms of viral IRES-driven translation. Trends Microbiol. 25, 546-561 (2017).
72. Paul, A. V. & Wimmer, E. Initiation of protein-primed picornavirus RNA synthesis. Virus Res. 206, 12-26 (2015).
73. Suhy, D. A., Giddings, T. H. & Kirkegaard, K. Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles. J. Virol. 74, 8953-8965 (2000).
74. Strating, J. R. P. M. & van Kuppeveld, F. J. M. Viral rewiring of cellular lipid metabolism to create membranous replication compartments. Curr. Opin. Cell Biol. 47, 24-33 (2017).
75. Ilnytska, O. et al. Enteroviruses harness the cellular endocytic machinery to remodel the host cell cholesterol landscape for effective viral replication. Cell Host Microbe 14, 281-293 (2013).
76. Ford Siltz, L. A. et al. New small-molecule inhibitors effectively blocking picornavirus replication. J. Virol. 88, 11091-11107 (2014).
77. Arita, M. Mechanism of poliovirus resistance to host phosphatidylinositol-4 kinase III ? inhibitor. ACS Infect. Dis. 2, 140-148 (2016).
78. Melia, C. et al. Escaping host factor PI4KB inhibition: enterovirus genomic RNA replication in the absence of replication organelles. Cell Rep. 21, 587-599 (2017).
79. Arita, M. Phosphatidylinositol-4 kinase III beta and oxysterol-binding protein accumulate unesterified cholesterol on poliovirus-induced membrane structure. Microbiol. Immunol. 58, 239-256 (2014).
80. Agirre, A., Barco, A., Carrasco, L. & Nieva, J. L. Viroporin-mediated membrane permeabilization: pore formation by nonstructural poliovirus 2B protein. J. Biol. Chem. 277, 40434-40441 (2002).
81. van Kuppeveld, F. J. M., de Jong, A. S., Melchers, W. J. G. & Willems, P. H. G. M. Enterovirus protein 2B po(u)res out the calcium: a viral strategy to survive? Trends Microbiol. 13, 41-44 (2005).
82. Tang, W.-F. et al. Reticulon 3 binds the 2C protein of enterovirus 71 and is required for viral replication. J. Biol. Chem. 282, 5888-5898 (2007).
83. Arita, M., Wakita, T. & Shimizu, H. Valosin-containing protein (VCP/p97) is required for poliovirus replication and is involved in cellular protein secretion pathway in poliovirus infection. J. Virol. 86, 5541-5553 (2012).
84. Jackson, W. T. et al. Subversion of cellular autophagosomal machinery by RNA viruses. PloS Biol. 3, 861-871 (2005).
85. Song, J. H. et al. Antiviral activity of gemcitabine against human rhinovirus in vitro and in vivo. Antiviral Res. 145, 6-13 (2017).
86. van der Linden, L. et al. The RNA template channel of the RNA-dependent RNA polymerase as a target for development of antiviral therapy of multiple genera within a virus family. PloS Pathog. 11, e1004733 (2015).
87. Zuo, J. et al. Fluoxetine is a potent inhibitor of coxsackievirus replication. Antimicrob. Agents Chemother. 56, 4838-4844 (2012).
88. Ulferts, R. et al. Selective serotonin reuptake inhibitor fluoxetine inhibits replication of human enteroviruses B and D by targeting viral protein 2C. Antimicrob. Agents Chemother. 57, 1952-1956 (2013).
89. Gofshteyn, J., Cárdenas, A. M. & Bearden, D. Treatment of chronic enterovirus encephalitis with fluoxetine in a patient with X-linked agammaglobulinemia. Pediatr. Neurol. 64, 94-98 (2016).
90. Guan, H. et al. Crystal structure of 2C helicase from enterovirus 71. Sci. Adv. 3, e1602573 (2017).
91. Spickler, C. et al. Phosphatidylinositol 4-kinase III beta is essential for replication of human rhinovirus and its inhibition causes a lethal phenotype in vivo. Antimicrob. Agents Chemother. 57, 3358-3368 (2013).
92. L amarche, M. J. et al. Anti-hepatitis C virus activity and toxicity of type III phosphatidylinositol-4-kinase beta inhibitors. Antimicrob. Agents Chemother. 56, 5149-5156 (2012).
93. Strating, J. R. P. M. et al. Itraconazole inhibits enterovirus replication by targeting the oxysterolbinding protein. Cell Rep. 10, 600-615 (2015).
94. Shim, A. et al. Therapeutic and prophylactic activity of itraconazole against human rhinovirus infection in a murine model. Sci. Rep. 6, 23110 (2016).
95. Jiang, P., Liu, Y., Ma, H.-C., Paul, A. V. & Wimmer, E. Picornavirus morphogenesis. Microbiol. Mol. Biol. Rev. 78, 418-437 (2014).
96. Geller, R., Vignuzzi, M., Andino, R. & Frydman, J. Evolutionary constraints on chaperone-mediated folding provide an antiviral approach refractory to development of drug resistance. Genes Dev. 21, 195-205 (2007).
97. Paul, A. V., Schultz, A., Pincus, S. E., Oroszlan, S. & Wimmer, E. Capsid protein VP4 of poliovirus is Nmyristoylated. Proc. Natl Acad. Sci. USA 84, 7827-7831 (1987).
98. Chow, M. et al. Myristylation of picornavirus capsid protein VP4 and its structural significance. Nature 327, 482-486 (1987).
99. Thibaut, H. J. et al. Binding of glutathione to enterovirus capsids is essential for virion morphogenesis. PloS Pathog. 10, e1004039 (2014).
100. Ma, H. C. et al. An interaction between glutathione and the capsid is required for the morphogenesis of C-cluster enteroviruses. PloS Pathog. 10, e1004052 (2014).
101. Basavappa, R. et al. Role and mechanism of the maturation cleavage of VP0 in poliovirus assembly: structure of the empty capsid assembly intermediate at 2. 9 A resolution. Protein Sci. 3, 1651-1669 (1994).
102. L iu, Y. et al. Direct interaction between two viral proteins, the nonstructural protein 2CATPase and the capsid protein VP3, is required for enterovirus morphogenesis. PloS Pathog. 6, e1001066 (2010).
103. Shakeel, S. et al. Genomic RNA folding mediates assembly of human parechovirus. Nat. Commun. 8, 5 (2017).
104. L ogan, G. et al. Deep sequencing of foot-and-mouth disease virus reveals RNA sequences involved in genome packaging. J. Virol. 92, e01159-17 (2017).
105. Tsou, Y.-L. et al. Heat shock protein 90: role in enterovirus 71 entry and assembly and potential target for therapy. PloS ONE 8, e77133 (2013).
106. Smith, A. D. & Dawson, H. Glutathione is required for efficient production of infectious picornavirus virions. Virology 353, 258-267 (2006).
107. Robinson, S. M. et al. Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PloS Pathog. 10, e1004045 (2014).
108. Bird, S. W., Maynard, N. D., Covert, M. W. & Kirkegaard, K. Nonlytic viral spread enhanced by autophagy components. Proc. Natl Acad. Sci. USA 111, 13081-13086 (2014).
109. Chen, Y. H. et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 160, 619-630 (2015).
110. Too, I. H. K. et al. Enterovirus 71 infection of motor neuron-like NSC-34 cells undergoes a non-lytic exit pathway. Sci. Rep. 6, 36983 (2016).
111. McKnight, K. L. et al. Protein composition of the hepatitis A virus quasi-envelope. Proc. Natl Acad. Sci. USA 114, 6587-6592 (2017).
112. Feng, Z. et al. A pathogenic picornavirus acquires an envelope by hijacking cellular membranes. Nature 496, 367-371 (2013).
113. Bandyopadhyay, A. S., Garon, J., Seib, K. & Orenstein, W. A. Polio vaccination: past, present and future. Future Microbiol. 10, 791-808 (2015).
114. Knowlson, S. et al. New strains intended for the production of inactivated polio vaccine at lowcontainment after eradication. PloS Pathog. 11, e1005316 (2015).
115. Pfeiffer, J. K. & Kirkegaard, K. A single mutation in poliovirus RNA-dependent RNA polymerase confers resistance to mutagenic nucleotide analogs via increased fidelity. Proc. Natl Acad. Sci. USA 100, 7289-7294 (2003).
116. Vignuzzi, M., Stone, J. K., Arnold, J. J., Cameron, C. E. & Andino, R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population. Nature 439, 344-348 (2006).
117. Xiao, Y. et al. RNA Recombination Enhances Adaptability and Is Required for Virus Spread and Virulence. Cell Host Microbe 19, 493-503 (2016).
118. Coleman, J. R. et al. Virus attenuation by genomescale changes in codon pair bias. Science 320, 1784-1787 (2008).
119. L ee, S. et al. A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques. Nat. Commun. 7, 12838 (2016).
120. Fox, H., Knowlson, S., Minor, P. D. & Macadam, A. J. Genetically thermo-stabilised, immunogenic poliovirus empty capsids; a strategy for non-replicating vaccines. PloS Pathog. 13, e1006117 (2017).
121. Adeyemi, O. O., Nicol, C., Stonehouse, N. J. & Rowlands, D. J. Increasing type-1 poliovirus capsid stability by thermal selection. J. Virol. 91, e01586-16 (2017).
122. Marsian, J. et al. Plant-made polio type 3 stabilized VLPs - a candidate synthetic polio vaccine. Nat. Commun. 8, 245 (2017).
123. Jiang, P. et al. Evidence for emergence of diverse polioviruses from C-cluster coxsackie A viruses and implications for global poliovirus eradication. Proc. Natl Acad. Sci. USA 104, 9457-9462 (2007).
124. Ho, M. et al. An epidemic of enterovirus 71 infection in Taiwan. N. Engl. J. Med. 341, 929-935 (1999).
125. L iu, S.-L. et al. Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. Rev. Med. Virol. 25, 115-128 (2015).
126. Xing, W. et al. Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. Lancet Infect. Dis. 14, 308-318 (2014).
127. Greninger, A. L. et al. A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012-2014): a retrospective cohort study. Lancet Infect. Dis. 3099, 10-12 (2015).
128. Messacar, K. et al. Acute flaccid myelitis: a clinical review of US cases 2012-2015. Ann. Neurol. 80, 326-338 (2016).
129. Pevear, D. C., Tull, T. M., Seipel, M. E. & Groarke, J. M. Activity of pleconaril against enteroviruses. Antimicrob. Agents Chemother. 43, 2109-2115 (1999).
130. De Palma, A. M. et al. Potential use of antiviral agents in polio eradication. Emerg. Infect. Dis. 14, 545-551 (2008).
131. Tijsma, A. et al. The capsid binder vapendavir and the novel protease inhibitor SG85 inhibit enterovirus 71 replication. Antimicrob. Agents Chemother. 58, 6990-6992 (2014).
132. Sun, L. et al. Antiviral activity of broad-spectrum and enterovirus-specific inhibitors against clinical isolates of enterovirus D68. Antimicrob. Agents Chemother. 59, 7782-7785 (2015).
133. Rhoden, E., Zhang, M., Nix, W. A. & Oberste, M. S. In vitro efficacy of antiviral compounds against enterovirus D68. Antimicrob. Agents Chemother. 59, 1-13 (2015).
134. Mello, C. et al. Multiple classes of antiviral agents exhibit in vitro activity against human rhinovirus type C. Antimicrob. Agents Chemother. 58, 1546-1555 (2014).
135. Patick, A. K. et al. In vitro antiviral activity of AG7088, a potent inhibitor of human rhinovirus 3 C protease. Antimicrob. Agents Chemother. 43, 2444-2450 (1999).
136. Feil, S. C. et al. An orally available 3-ethoxybenzisoxazole capsid binder with clinical activity against human rhinovirus. ACS Med. Chem. Lett. 3, 303-307 (2012).
137. Rhoden, E., Liu, H.-M., Wang-Chern, S. & Oberste, M. S. Anti-poliovirus activity of protease inhibitor AG-7404, and assessment of in vitro activity in combination with antiviral capsid inhibitor compounds. Antiviral Res. 98, 186-191 (2013).
138. Buontempo, P. J. et al. SCH 48973: a potent, broadspectrum, antienterovirus compound. Antimicrob. Agents Chemother. 41, 1220-1225 (1997).
139. Collett, M. S. et al. Antiviral activity of pocapavir in a randomized, blinded, placebo-controlled human oral poliovirus vaccine challenge model. J. Infect. Dis. 215, 335-343 (2017).
140. De Colibus, L. et al. More-powerful virus inhibitors from structure-based analysis of HEV71 capsidbinding molecules. Nat. Struct. Mol. Biol. 21, 282-288 (2014).
141. Patick, A. K. et al. In vitro antiviral activity and singledose pharmacokinetics in humans of a novel, orally bioavailable inhibitor of human rhinovirus 3 C protease. Antimicrob. Agents Chemother. 49, 2267-2275 (2005).
142. Ma, G.-H. et al. Identification and biochemical characterization of DC07090 as a novel potent small molecule inhibitor against human enterovirus 71 3 C protease by structure-based virtual screening. Eur. J. Med. Chem. 124, 981-991 (2016).
143. Kang, H. et al. Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses. Antiviral Res. 124, 1-10 (2015).
144. Deng, C.-L. et al. Inhibition of enterovirus 71 by adenosine analog NITD008. J. Virol. 88, 11915-11923 (2014).
145. Crotty, S. et al. The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen. Nat. Med. 6, 1375-1379 (2000).
146. Andersen, D., Murray, B., Robins, R. & North, J. In vitro antiviral activity of ribavirin against picornaviruses. Antivir. Chem. Chemother. 3, 361-370 (1992).
147. Harrison, D. N., Gazina, E. V., Purcell, D. F., Anderson, D. A. & Petrou, S. Amiloride derivatives inhibit coxsackievirus B3 RNA replication. J. Virol. 82, 1465-1473 (2008).
148. Ulferts, R. et al. Screening of a library of FDA-approved drugs identifies several enterovirus replication inhibitors that target viral protein 2C. Antimicrob. Agents Chemother. 60, 2627-2638 (2016).
149. Hadaschik, D., Klein, M., Zimmermann, H., Eggers, H. J. & Nelsen-Salz, B. Dependence of echovirus 9 on the enterovirus RNA replication inhibitor 2-(alpha-Hydroxybenzyl)-benzimidazole maps to nonstructural protein 2C. J. Virol. 73, 10536-10539 (1999).
150. van der Schaar, H. M. et al. A novel, broad-spectrum inhibitor of enterovirus replication that targets host cell factor phosphatidylinositol 4-kinase IIIbeta. Antimicrob. Agents Chemother. 57, 4971-4981 (2013).
151. Arita, M., Dobrikov, G., Purstinger, G. & Galabov, A. S. Allosteric regulation of phosphatidylinositol 4-kinase III beta by an antipicornavirus compound MDL-860. ACS Infect. Dis. 3, 585-594 (2017).
152. Torney, H. L., Dulworth, J. K. & Steward, D. L. Antiviral activity and mechanism of action of 2-(3, 4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860). Antimicrob. Agents Chemother. 22, 635-638 (1982).
153. Albulescu, L. et al. Broad-range inhibition of enterovirus replication by OSW-1, a natural compound targeting OSBP. Antiviral Res. 117, 110-114 (2015).
154. Tan, Y. W., Hong, W. J. & Chu, J. J. H. Inhibition of enterovirus VP4 myristoylation is a potential antiviral strategy for hand, foot and mouth disease. Antiviral Res. 133, 191-195 (2016).
155. Yamayoshi, S. et al. Human SCARB2-dependent infection by coxsackievirus A7, A14, and A16 and enterovirus 71. J. Virol. 86, 5686-5696 (2012).
156. Nishimura, Y. & Shimizu, H. Cellular receptors for human enterovirus species A. Front. Microbiol. 3, 105 (2012).
157. Yamayoshi, S., Fujii, K. & Koike, S. Receptors for enterovirus 71. Emerg. Microbes Infect. 3, e53 (2014).
158. Royston, L. & Tapparel, C. Rhinoviruses and respiratory enteroviruses: not as simple as ABC. Viruses 8, E16 (2016).
159. Baggen, J. et al. Enterovirus D68 receptor requirements unveiled by haploid genetics. Proc. Natl Acad. Sci. USA 113, 1399-1404 (2016).
160. Hofer, F. et al. Members of the low density lipoprotein receptor family mediate cell entry of a minor-group common cold virus. Proc. Natl Acad. Sci. USA 91, 1839-1842 (1994).
161. Bergelson, J. M. et al. Decay-accelerating factor (CD55), a glycosylphosphatidylinositol-anchored complement regulatory protein, is a receptor for several echoviruses. Proc. Natl Acad. Sci. USA 91, 6245-6248 (1994).
162. Martino, T. A. et al. The coxsackie-adenovirus receptor (CAR) is used by reference strains and clinical isolates representing all six serotypes of coxsackievirus group B and by swine vesicular disease virus. Virology 271, 99-108 (2000).
163. Williams, Ç. H. et al. Integrin ?v?6 Is an RGDDependent Receptor for Coxsackievirus A9. J. Virol. 78, 6967-6973 (2004).
164. Bergelson, J. M., Shepley, M. P., Chan, B. M., Hemler, M. E. & Finberg, R. W. Identification of the integrin VLA-2 as a receptor for echovirus 1. Science 255, 1718-1720 (1992).