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Archives of Virology

, Volume 157, Issue 4, pp 669–679 | Cite as

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

  • Guofeng Zhang
  • Feng Zhou
  • Bin Gu
  • Chuanling Ding
  • Dongju Feng
  • Fangyi Xie
  • Jinfeng Wang
  • Chun Zhang
  • Qingxian Cao
  • Yinlai Deng
  • Weixing HuEmail author
  • Kun YaoEmail author
Original Article

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.

Keywords

Antiviral Activity Infected Mouse EV71 Infection Spinal Ganglion Lassa Fever 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

References

  1. 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 10:778–790PubMedCrossRefGoogle Scholar
  2. 2.
    Rotbart HA, O’Connell JF, McKinlay MA (1998) Treatment of human enterovirus infections. Antiviral Res 38:1–14PubMedCrossRefGoogle Scholar
  3. 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 295–325CrossRefGoogle Scholar
  4. 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 129:304–309PubMedCrossRefGoogle Scholar
  5. 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 9:461–468PubMedGoogle Scholar
  6. 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 354:1682–1686PubMedCrossRefGoogle Scholar
  7. 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–e252PubMedCrossRefGoogle Scholar
  8. 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 49:100–104PubMedCrossRefGoogle Scholar
  9. 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 341:936–942PubMedCrossRefGoogle Scholar
  10. 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 43:99–104Google Scholar
  11. 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 28:904–910PubMedCrossRefGoogle Scholar
  12. 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 188:564–570PubMedCrossRefGoogle Scholar
  13. 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 18:1092–1096PubMedCrossRefGoogle Scholar
  14. 14.
    Lum LC, Wong KT, Lam SK, Chua KB, Goh AY (1998) Neurogenic pulmonary oedema and enterovirus 71 encephalomyelitis. Lancet 352:1391PubMedCrossRefGoogle Scholar
  15. 15.
    Wu KX, Ng MM, Chu JJ (2010) Developments towards antiviral therapies against enterovirus 71. Drug Discov Today 15:1041–1051PubMedCrossRefGoogle Scholar
  16. 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 197:854–857PubMedCrossRefGoogle Scholar
  17. 17.
    Pevear DC, Tull TM, Seipel ME, Groarke JM (1999) Activity of pleconaril against enteroviruses. Antimicrob Agents Chemother 43:2109–2115PubMedGoogle Scholar
  18. 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 39:9–15PubMedCrossRefGoogle Scholar
  19. 19.
    Snell NJ (2001) Ribavirin–current status of a broad spectrum antiviral agent. Expert Opin Pharmacother 2:1317–1324PubMedCrossRefGoogle Scholar
  20. 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 139:1612–1618PubMedCrossRefGoogle Scholar
  21. 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 23:44–46PubMedGoogle Scholar
  22. 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 5:2500–2511Google Scholar
  23. 23.
    Reina J, Ballesteros F (2000) Pleconaril, a new aniviral drug with activity against picornavirus. Rev Esp Quimioter 13:257–262PubMedGoogle Scholar
  24. 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–E14PubMedCrossRefGoogle Scholar
  25. 25.
    Rotbart HA, Webster AD (2001) Treatment of potentially life-threatening enterovirus infections with pleconaril. Clin Infect Dis 32:228–235PubMedCrossRefGoogle Scholar
  26. 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 85:69–77PubMedCrossRefGoogle Scholar
  27. 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 67:532–542PubMedCrossRefGoogle Scholar
  28. 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 7:523–528PubMedCrossRefGoogle Scholar
  29. 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 53:2740–2747PubMedCrossRefGoogle Scholar
  30. 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 40:2327–2331PubMedGoogle Scholar
  31. 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 83:6477–6483PubMedCrossRefGoogle Scholar
  32. 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 67:162–169PubMedCrossRefGoogle Scholar
  33. 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 78:7916–7924PubMedCrossRefGoogle Scholar
  34. 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 73:1941–1948PubMedGoogle Scholar
  35. 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 317:145–153PubMedCrossRefGoogle Scholar
  36. 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 165:121–124PubMedCrossRefGoogle Scholar
  37. 37.
    Chang LY, Huang YC, Lin TY (1998) Fulminant neurogenic pulmonary oedema with hand, foot, and mouth disease. Lancet 352:367–368PubMedCrossRefGoogle Scholar
  38. 38.
    Ren R, Racaniello VR (1992) Poliovirus spreads from muscle to the central nervous system by neural pathways. J Infect Dis 166:747–752PubMedCrossRefGoogle Scholar
  39. 39.
    Hsiung GD, Wang JR (2000) Enterovirus infections with special reference to enterovirus 71. J Microbiol Immunol Infect 33:1–8PubMedGoogle Scholar
  40. 40.
    Jubelt B (2003) Pleconaril for infantile enterovirus meningitis. Curr Neurol Neurosci Rep 3:459–460PubMedCrossRefGoogle Scholar
  41. 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 60:1651–1656PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Guofeng Zhang
    • 1
    • 2
  • Feng Zhou
    • 1
  • Bin Gu
    • 1
    • 2
  • Chuanling Ding
    • 3
  • Dongju Feng
    • 1
  • Fangyi Xie
    • 1
  • Jinfeng Wang
    • 1
  • Chun Zhang
    • 1
    • 2
  • Qingxian Cao
    • 4
  • Yinlai Deng
    • 4
  • Weixing Hu
    • 2
    Email author
  • Kun Yao
    • 1
    Email author
  1. 1.Department of Microbiology and ImmunityNanjing Medical UniversityNanjingChina
  2. 2.Department of NeurosurgeryThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  3. 3.Tumor Immunolobiology Program, James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA
  4. 4.Jiangsu Wuzhong GroupSuzhouChina

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