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Journal of Virology, July 2006, p. 6430-6440, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00044-06

Reverse Genetic Generation of Recombinant Zaire Ebola Viruses Containing Disrupted IRF-3 Inhibitory Domains Results in Attenuated Virus Growth In Vitro and Higher Levels of IRF-3 Activation without Inhibiting Viral Transcription or Replication

Amy L. Hartman, Jason E. Dover, Jonathan S. Towner, and Stuart T. Nichol*

Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., MS G-14, Atlanta, Georgia 30329

Received 6 January 2006/ Accepted 18 April 2006

The VP35 protein of Zaire Ebola virus is an essential component of the viral RNA polymerase complex and also functions to antagonize the cellular type I interferon (IFN) response by blocking activation of the transcription factor IRF-3. We previously mapped the IRF-3 inhibitory domain within the C terminus of VP35. In the present study, we show that mutations that disrupt the IRF-3 inhibitory function of VP35 do not disrupt viral transcription/replication, suggesting that the two functions of VP35 are separable. Second, using reverse genetics, we successfully recovered recombinant Ebola viruses containing mutations within the IRF-3 inhibitory domain. Importantly, we show that the recombinant viruses were attenuated for growth in cell culture and that they activated IRF-3 and IRF-3-inducible gene expression at levels higher than that for Ebola virus containing wild-type VP35. In the context of Ebola virus pathogenesis, VP35 may function to limit early IFN-ß production and other antiviral signals generated from cells at the primary site of infection, thereby slowing down the host's ability to curb virus replication and induce adaptive immunity.

* Corresponding author. Mailing address: Special Pathogens Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., MS G-14, Atlanta, GA 30329. Phone: (404) 639-1115. Fax: (404) 639-1118. E-mail: stn1{at}cdc.gov.

Journal of Virology, July 2006, p. 6430-6440, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.00044-06




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