Skip to main content

Advertisement

SpringerLink
Log in

In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection

  • Original Article
  • Published:
Archives of Virology Aims and scope Submit manuscript

Abstract

Enterovirus 71(EV71) causes recurring outbreaks of hand, foot and mouth disease and encephalitis leading to complications or death in young children. More effective antiviral drugs are needed to prevent or reduce EV71-related disease and complications. However, there are no standard models currently in use to evaluate activity against EV71 infection both in vitro and in vivo. In this study, the activity of ribavirin and pleconaril against EV71 infection was evaluated in two models. An in vitro EV71 infection model was developed in RD cells, and an in vivo EV71 infection model was applied. Ribavirin and pleconaril effectively increased the viability of infected cells. Pleconaril reduced the morbidity and mortality of one-day-old infected mice, but ribavirin did not protect the infected mice. In all, the results demonstrated that infected cells and infected mice can be used to evaluate antiviral activity of ribavirin and pleconaril against EV71 infection in vitro and in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH (2010) Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10:778–790

    Article  PubMed  Google Scholar 

  2. Rotbart HA, O’Connell JF, McKinlay MA (1998) Treatment of human enterovirus infections. Antiviral Res 38:1–14

    Article  PubMed  CAS  Google Scholar 

  3. Chang LY, Shih SR, Huang LM, Lin TY (2007) Enterovirus 71 Encephalitis. In: Fong IW, Alibeck K (eds) New and evolving infections of the 21st Century. Springer, New York, pp 295–325

    Chapter  Google Scholar 

  4. Schmidt NJ, Lennette EH, Ho HH (1974) An apparently new enterovirus isolated from patients with disease of the central nervous system. J Infect Dis 129:304–309

    Article  PubMed  CAS  Google Scholar 

  5. Cardosa MJ, Perera D, Brown BA, Cheon D, Chan HM, Chan KP, Cho H, McMinn P (2003) Molecular epidemiology of human enterovirus 71 strains and recent outbreaks in the Asia-Pacific region: comparative analysis of the VP1 and VP4 genes. Emerg Infect Dis 9:461–468

    PubMed  Google Scholar 

  6. Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, Shih SR, Ning HC, Hwang MS, Wang HS, Lee CY (1999) Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 354:1682–1686

    Article  PubMed  CAS  Google Scholar 

  7. Chen KT, Chang HL, Wang ST, Cheng YT, Yang JY (2007) Epidemiologic features of hand-foot-mouth disease and herpangina caused by enterovirus 71 in Taiwan, 1998–2005. Pediatrics 120:e244–e252

    Article  PubMed  Google Scholar 

  8. Mao LX, Wu B, Bao WX, Han FA, Xu L, Ge QJ, Yang J, Yuan ZH, Miao CH, Huang XX, Zhang C, Xu H (2010) Epidemiology of hand, foot, and mouth disease and genotype characterization of Enterovirus 71 in Jiangsu, China. J Clin Virol 49:100–104

    Article  PubMed  Google Scholar 

  9. Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF (1999) Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341:936–942

    Article  PubMed  CAS  Google Scholar 

  10. Chen SP, Huang YC, Li WC, Chiu CH, Huang CG, Tsao KC, Lin TY (2010) Comparison of clinical features between coxsackievirus A2 and enterovirus 71 during the enterovirus outbreak in Taiwan, 2008: a children’s hospital experience. J Microbiol Immunol 43:99–104

    Google Scholar 

  11. Lee T-C, Guo H-R, Su H-JJ, Yang Y-C, Chang H-L, Chen K-T (2009) Diseases caused by Enterovirus 71 Infection. Pediatr Infect Dis J 28:904–910

    Article  PubMed  Google Scholar 

  12. Wang SM, Lei HY, Huang KJ, Wu JM, Wang JR, Yu CK, Su IJ, Liu CC (2003) Pathogenesis of enterovirus 71 brainstem encephalitis in pediatric patients: roles of cytokines and cellular immune activation in patients with pulmonary edema. J Infect Dis 188:564–570

    Article  PubMed  CAS  Google Scholar 

  13. Chang LY, Lin TY, Huang YC, Tsao KC, Shih SR, Kuo ML, Ning HC, Chung PW, Kang CM (1999) Comparison of enterovirus 71 and coxsackie-virus A16 clinical illnesses during the Taiwan enterovirus epidemic, 1998. Pediatr Infect Dis J 18:1092–1096

    Article  PubMed  CAS  Google Scholar 

  14. Lum LC, Wong KT, Lam SK, Chua KB, Goh AY (1998) Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis. Lancet 352:1391

    Article  PubMed  CAS  Google Scholar 

  15. Wu KX, Ng MM, Chu JJ (2010) Developments towards antiviral therapies against enterovirus 71. Drug Discov Today 15:1041–1051

    Article  PubMed  CAS  Google Scholar 

  16. Li ZH, Li CM, Ling P, Shen FH, Chen SH, Liu CC, Yu CK, Chen SH (2008) Ribavirin reduces mortality in enterovirus 71-infected mice by decreasing viral replication. J Infect Dis 197:854–857

    Article  PubMed  CAS  Google Scholar 

  17. Pevear DC, Tull TM, Seipel ME, Groarke JM (1999) Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 43:2109–2115

    PubMed  CAS  Google Scholar 

  18. Gu CJ, Zheng CY, Zhang Q, Shi LL, Li Y, Qu SF (2006) An antiviral mechanism investigated with ribavirin as an RNA virus mutagen for foot-and-mouth disease virus. J Biochem Mol Biol 39:9–15

    Article  PubMed  CAS  Google Scholar 

  19. Snell NJ (2001) Ribavirin–current status of a broad spectrum antiviral agent. Expert Opin Pharmacother 2:1317–1324

    Article  PubMed  CAS  Google Scholar 

  20. Kamar N, Rostaing L, Abravanel F, Garrouste C, Lhomme S, Esposito L, Basse G, Cointault O, Ribes D, Nogier MB, Alric L, Peron JM, Izopet J (2010) Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. Gastroenterology 139:1612–1618

    Article  PubMed  CAS  Google Scholar 

  21. Zhang Y, Zhu Z, Zhu SL, An HQ, Yang ZH, Guo XB, Xu WB (2009) In vitro study on the effect of ribavirin reducing the EV71 replication. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 23:44–46

    PubMed  Google Scholar 

  22. Hsu HW, Wang JH, Liu CL, Chen CS, Wang YC (2011) Anti-enterovirus 71 activity screening of Taiwanese folk medicinal plants and immune modulation of Ampelopsis brevipedunculata (Maxim.) Trautv against the virus. Afr J Microbiol Res 5:2500–2511

    Google Scholar 

  23. Reina J, Ballesteros F (2000) Pleconaril, a new aniviral drug with activity against picornavirus. Rev Esp Quimioter 13:257–262

    PubMed  CAS  Google Scholar 

  24. Nowak-Wegrzyn A, Phipatanakul W, Winkelstein JA, Forman MS, Lederman HM (2001) Successful treatment of enterovirus infection with the use of pleconaril in 2 infants with severe combined immunodeficiency. Clin Infect Dis 32:E13–E14

    Article  PubMed  CAS  Google Scholar 

  25. Rotbart HA, Webster AD (2001) Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis 32:228–235

    Article  PubMed  CAS  Google Scholar 

  26. Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY (2004) A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 85:69–77

    Article  PubMed  CAS  Google Scholar 

  27. Ong KC, Badmanathan M, Devi S, Leong KL, Cardosa MJ, Wong KT (2008) Pathologic characterization of a murine model of human enterovirus 71 encephalomyelitis. J Neuropathol Exp Neurol 67:532–542

    Article  PubMed  Google Scholar 

  28. Yu CK, Chen CC, Chen CL, Wang JR, Liu CC, Yan JJ, Su IJ (2000) Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice. J Biomed Sci 7:523–528

    Article  PubMed  CAS  Google Scholar 

  29. Chen TC, Chang HY, Lin PF, Chern JH, Hsu JT, Chang CY, Shih SR (2009) Novel antiviral agent DTriP-22 targets RNA-dependent RNA polymerase of enterovirus 71. Antimicrob Agents Chemother 53:2740–2747

    Article  PubMed  CAS  Google Scholar 

  30. O’Brien WJ, Taylor JL, Ankel H, Sitenga G (1996) Assessment of antiviral activity, efficacy, and toxicity of prostaglandin A2 in a rabbit model of herpetic keratitis. Antimicrob Agents Chemother 40:2327–2331

    PubMed  Google Scholar 

  31. Lin YW, Chang KC, Kao CM, Chang SP, Tung YY, Chen SH (2009) Lymphocyte and antibody responses reduce enterovirus 71 lethality in mice by decreasing tissue viral loads. J Virol 83:6477–6483

    Article  PubMed  CAS  Google Scholar 

  32. Wong KT, Munisamy B, Ong KC, Kojima H, Noriyo N, Chua KB, Ong BB, Nagashima K (2008) The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways. J Neuropathol Exp Neurol 67:162–169

    Article  PubMed  Google Scholar 

  33. Wang YF, Chou CT, Lei HY, Liu CC, Wang SM, Yan JJ, Su IJ, Wang JR, Yeh TM, Chen SH, Yu CK (2004) A mouse-adapted enterovirus 71 strain causes neurological disease in mice after oral infection. J Virol 78:7916–7924

    Article  PubMed  CAS  Google Scholar 

  34. Oberste MS, Maher K, Kilpatrick DR, Pallansch MA (1999) Molecular evolution of the human enteroviruses: correlation of serotype with VP1 sequence and application to picornavirus classification. J Virol 73:1941–1948

    PubMed  CAS  Google Scholar 

  35. Rossmann MG, Arnold E, Erickson JW, Frankenberger EA, Griffith JP, Hecht HJ, Johnson JE, Kamer G, Luo M, Mosser AG et al (1985) Structure of a human common cold virus and functional relationship to other picornaviruses. Nature 317:145–153

    Article  PubMed  CAS  Google Scholar 

  36. Lin HT, Tsai HY, Liu CP, Yuan TT (2010) Comparability of bovine virus titers obtained by TCID50/ml and FAID50/ml. J Virol Methods 165:121–124

    Article  PubMed  CAS  Google Scholar 

  37. Chang LY, Huang YC, Lin TY (1998) Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet 352:367–368

    Article  PubMed  CAS  Google Scholar 

  38. Ren R, Racaniello VR (1992) Poliovirus spreads from muscle to the central nervous system by neural pathways. J Infect Dis 166:747–752

    Article  PubMed  CAS  Google Scholar 

  39. Hsiung GD, Wang JR (2000) Enterovirus infections with special reference to enterovirus 71. J Microbiol Immunol Infect 33:1–8

    PubMed  CAS  Google Scholar 

  40. Jubelt B (2003) Pleconaril for infantile enterovirus meningitis. Curr Neurol Neurosci Rep 3:459–460

    Article  PubMed  Google Scholar 

  41. Nolan MA, Craig ME, Lahra MM, Rawlinson WD, Prager PC, Williams GD, Bye AM, Andrews PI (2003) Survival after pulmonary edema due to enterovirus 71 encephalitis. Neurology 60:1651–1656

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Science and Technology Major Project of China (NO.2009zx09103-005), Professor Zhiyang Shi, who kindly provided virus from the Key Lab of Enteric Pathogenic Microbiology of the Chinese Ministry of Health, and Qingxian Cao and Yinlai Deng from the Jiangsu Wu Zhong Group.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunity, Nanjing Medical University, 140# Hanzhong Road, Nanjing, 210029, Jiangsu, China

    Guofeng Zhang, Feng Zhou, Bin Gu, Dongju Feng, Fangyi Xie, Jinfeng Wang, Chun Zhang & Kun Yao

  2. Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300# Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Guofeng Zhang, Bin Gu, Chun Zhang & Weixing Hu

  3. Tumor Immunolobiology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA

    Chuanling Ding

  4. Jiangsu Wuzhong Group, 110# Dongwubeilu, Suzhou, 215128, China

    Qingxian Cao & Yinlai Deng

Authors
  1. Guofeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bin Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chuanling Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongju Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fangyi Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinfeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qingxian Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yinlai Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Weixing Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kun Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Weixing Hu or Kun Yao.

Additional information

G. Zhang and F. Zhou contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, G., Zhou, F., Gu, B. et al. In vitro and in vivo evaluation of ribavirin and pleconaril antiviral activity against enterovirus 71 infection. Arch Virol 157, 669–679 (2012). https://doi.org/10.1007/s00705-011-1222-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00705-011-1222-6

Keywords

Search

Navigation