1887

Abstract

The human MxA protein is a type I and III interferon (IFN)-induced protein with proven antiviral activity against RNA viruses. In this study, we investigated the effect of MxA expression on the replication of West Nile Virus strain Kunjin (WNV). Pretreatment of A549 cells with IFN- lead to increased expression of MxA, which contributed to inhibition of WNV replication and secretion. However, in Vero cells stably expressing the MxA protein, WNV replication, maturation and secretion was not inhibited. Biochemical and subcellular localization studies of WNV proteins and MxA suggest that the MxA activity was not compromised by a flavivirus-encoded antagonist. Instead, we show that characteristic membranous structures induced during WNV replication provide partial protection from MxA, possibly by ‘hiding’ WNV replication components. This distinct compartmentalization of viral replication and components of the cellular antiviral response may be an evolutionary mechanism by which flaviviruses can hide from host surveillance.

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2007-11-01
2024-12-05
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References

  1. Chieux V., Chehadeh W., Harvey J., Haller O., Wattre P., Hober D. 2001; Inhibition of coxsackievirus B4 replication in stably transfected cells expressing human MxA protein. Virology 283:84–92 [CrossRef]
    [Google Scholar]
  2. Diamond M. S., Harris E. 2001; Interferon inhibits dengue virus infection by preventing translation of viral RNA through a PKR-independent mechanism. Virology 289:297–311 [CrossRef]
    [Google Scholar]
  3. Flohr F., Schneider-Schaulies S., Haller O., Kochs G. 1999; The central interactive region of human MxA GTPase is involved in GTPase activation and interaction with viral target structures. FEBS Lett 463:24–28 [CrossRef]
    [Google Scholar]
  4. Frese M., Kochs G., Meier-Dieter U., Siebler J., Haller O. 1995; Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus. J Virol 69:3904–3909
    [Google Scholar]
  5. Frese M., Pietschmann T., Moradpour D., Haller O., Bartenschlager R. 2001; Interferon- α inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway. J Gen Virol 82:723–733
    [Google Scholar]
  6. Goodbourn S., Didcock L., Randall R. E. 2000; Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81:2341–2364
    [Google Scholar]
  7. Guo J. T., Hayashi J., Seeger C. 2005; West Nile virus inhibits the signal transduction pathway of alpha interferon. J Virol 79:1343–1350 [CrossRef]
    [Google Scholar]
  8. Haller O., Kochs G. 2002; Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3:710–717 [CrossRef]
    [Google Scholar]
  9. Holzinger D., Jorns C., Stertz S., Boisson-Dupuis S., Thimme R., Weidmann M., Casanova J. L., Haller O., Kochs G. 2007; Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling. J Virol 81:7776–7785 [CrossRef]
    [Google Scholar]
  10. Khromykh A. A., Sedlak P. L., Guyatt K. J., Hall R. A., Westaway E. G. 1999; Efficient trans -complementation of the flavivirus Kunjin NS5 protein but not of the NS1 protein requires its coexpression with other components of the viral replicase. J Virol 73:10272–10280
    [Google Scholar]
  11. Lanciotti R. S., Roehrig J. T., Deubel V., Smith J., Parker M., Steele K., Crise B., Volpe K. E., Crabtree M. B. other authors 1999; Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States. Science 286:2333–2337 [CrossRef]
    [Google Scholar]
  12. Landis H., Simon-Jodicke A., Kloti A., Di Paolo C., Schnorr J. J., Schneider-Schaulies S., Hefti H. P., Pavlovic J. 1998; Human MxA protein confers resistance to Semliki Forest virus and inhibits the amplification of a Semliki Forest virus-based replicon in the absence of viral structural proteins. J Virol 72:1516–1522
    [Google Scholar]
  13. Liu W. J., Sedlak P. L., Kondratieva N., Khromykh A. A. 2002; Complementation analysis of the flavivirus Kunjin NS3 and NS5 proteins defines the minimal regions essential for formation of a replication complex and shows a requirement of NS3 in cis for virus assembly. J Virol 76:10766–10775 [CrossRef]
    [Google Scholar]
  14. Liu W. J., Chen H. B., Khromykh A. A. 2003; Molecular and functional analyses of Kunjin virus infectious cDNA clones demonstrate the essential roles for NS2A in virus assembly and for a nonconservative residue in NS3 for RNA replication. J Virol 77:7804–7813 [CrossRef]
    [Google Scholar]
  15. Lobigs M., Mullbacher A., Wang Y., Pavy M., Lee E. 2003; Role of type I and type II interferon responses in recovery from infection with an encephalitic flavivirus. J Gen Virol 84:567–572 [CrossRef]
    [Google Scholar]
  16. Mackenzie J. M., Westaway E. G. 2001; Assembly and maturation of the flavivirus Kunjin virus appear to occur in the rough endoplasmic reticulum and along the secretory pathway, respectively. J Virol 75:10787–10799 [CrossRef]
    [Google Scholar]
  17. Mackenzie J. S., Lindsay M. D., Coelen R. J., Broom A. K., Hall R. A., Smith D. W. 1994; Arboviruses causing human disease in the Australasian zoogeographic region. Arch Virol 136:447–467 [CrossRef]
    [Google Scholar]
  18. Mackenzie J. M., Khromykh A. A., Jones M. K., Westaway E. G. 1998; Subcellular localization and some biochemical properties of the flavivirus Kunjin nonstructural proteins NS2A and NS4A. Virology 245:203–215 [CrossRef]
    [Google Scholar]
  19. Mackenzie J. M., Jones M. K., Westaway E. G. 1999; Markers for trans -Golgi membranes and the intermediate compartment localize to induced membranes with distinct replication functions in flavivirus-infected cells. J Virol 73:9555–9567
    [Google Scholar]
  20. Marschall M., Zach A., Hechtfischer A., Foerst G., Meier-Ewert H., Haller O. 2000; Inhibition of influenza C viruses by human MxA protein. Virus Res 67:179–188 [CrossRef]
    [Google Scholar]
  21. Mundt E. 2007; Human MxA protein confers resistance to double-stranded RNA viruses of two virus families. J Gen Virol 88:1319–1323 [CrossRef]
    [Google Scholar]
  22. Pavlovic J., Zurcher T., Haller O., Staeheli P. 1990; Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 64:3370–3375
    [Google Scholar]
  23. Pavlovic J., Haller O., Staeheli P. 1992; Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J Virol 66:2564–2569
    [Google Scholar]
  24. Ponten A., Sick C., Weeber M., Haller O., Kochs G. 1997; Dominant-negative mutants of human MxA protein: domains in the carboxy-terminal moiety are important for oligomerization and antiviral activity. J Virol 71:2591–2599
    [Google Scholar]
  25. Reichelt M., Stertz S., Krijnse-Locker J., Haller O., Kochs G. 2004; Missorting of LaCrosse virus nucleocapsid protein by the interferon-induced MxA GTPase involves smooth ER membranes. Traffic 5:772–784 [CrossRef]
    [Google Scholar]
  26. Samuel M. A., Diamond M. S. 2005; Alpha/beta interferon protects against lethal West Nile virus infection by restricting cellular tropism and enhancing neuronal survival. J Virol 79:13350–13361 [CrossRef]
    [Google Scholar]
  27. Schwemmle M., Weining K. C., Richter M. F., Schumacher B., Staeheli P. 1995; Vesicular stomatitis virus transcription inhibited by purified MxA protein. Virology 206:545–554 [CrossRef]
    [Google Scholar]
  28. Shi P. Y., Tilgner M., Lo M. K., Kent K. A., Bernard K. A. 2002; Infectious cDNA clone of the epidemic West Nile virus from New York City. J Virol 76:5847–5856 [CrossRef]
    [Google Scholar]
  29. Spiegel M., Pichlmair A., Muhlberger E., Haller O., Weber F. 2004; The antiviral effect of interferon-beta against SARS-coronavirus is not mediated by MxA protein. J Clin Virol 30:211–213 [CrossRef]
    [Google Scholar]
  30. Suzuki F., Arase Y., Suzuki Y., Tsubota A., Akuta N., Hosaka T., Someya T., Kobayashi M., Saitoh S. other authors 2004; Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection. J Viral Hepat 11:271–276 [CrossRef]
    [Google Scholar]
  31. Warke R. V., Xhaja K., Martin K. J., Fournier M. F., Shaw S. K., Brizuela N., de Bosch N., Lapointe D., Ennis F. A. other authors 2003; Dengue virus induces novel changes in gene expression of human umbilical vein endothelial cells. J Virol 77:11822–11832 [CrossRef]
    [Google Scholar]
  32. Westaway E. G., Khromykh A. A., Kenney M. T., Mackenzie J. M., Jones M. K. 1997a; Proteins C and NS4B of the flavivirus Kunjin translocate independently into the nucleus. Virology 234:31–41 [CrossRef]
    [Google Scholar]
  33. Westaway E. G., Mackenzie J. M., Kenney M. T., Jones M. K., Khromykh A. A. 1997b; Ultrastructure of Kunjin virus-infected cells: colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures. J Virol 71:6650–6661
    [Google Scholar]
  34. Zhao H., De B. P., Das T., Banerjee A. K. 1996; Inhibition of human parainfluenza virus-3 replication by interferon and human MxA. Virology 220:330–338 [CrossRef]
    [Google Scholar]
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