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Journal of Virology, September 2008, p. 8965-8977, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00853-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human Parainfluenza Virus Type 1 C Proteins Are Nonessential Proteins That Inhibit the Host Interferon and Apoptotic Responses and Are Required for Efficient Replication in Nonhuman Primates{triangledown}

Emmalene J. Bartlett,1,{dagger} Ann-Marie Cruz,1,{dagger} Janice Esker,1 Adam Castaño,1 Henrick Schomacker,1 Sonja R. Surman,1 Margaret Hennessey,2,3 Jim Boonyaratanakornkit,1 Raymond J. Pickles,2,3 Peter L. Collins,1 Brian R. Murphy,1 and Alexander C. Schmidt1*

Laboratory of Infectious Diseases, Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland 20892-8007,1 Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248,2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-72483

Received 22 April 2008/ Accepted 1 July 2008

Recombinant human parainfluenza virus type 1 (rHPIV1) was modified to create rHPIV1-P(C–), a virus in which expression of the C proteins (C', C, Y1, and Y2) was silenced without affecting the amino acid sequence of the P protein. Infectious rHPIV1-P(C–) was readily recovered from cDNA, indicating that the four C proteins were not essential for virus replication. Early during infection in vitro, rHPIV1-P(C–) replicated as efficiently as wild-type (wt) HPIV1, but its titer subsequently decreased coincident with the onset of an extensive cytopathic effect not observed with wt rHPIV1. rHPIV1-P(C–) infection, but not wt rHPIV1 infection, induced caspase 3 activation and nuclear fragmentation in LLC-MK2 cells, identifying the HPIV1 C proteins as inhibitors of apoptosis. In contrast to wt rHPIV1, rHPIV1-P(C–) and rHPIV1-CF170S, a mutant encoding an F170S substitution in C, induced interferon (IFN) and did not inhibit IFN signaling in vitro. However, only rHPIV1-P(C–) induced apoptosis. Thus, the anti-IFN and antiapoptosis activities of HPIV1 were separable: both activities are disabled in rHPIV1-P(C–), whereas only the anti-IFN activity is disabled in rHPIV1-CF170S. In African green monkeys (AGMs), rHPIV1-P(C–) was considerably more attenuated than rHPIV1-CF170S, suggesting that disabling the anti-IFN and antiapoptotic activities of HPIV1 had additive effects on attenuation in vivo. Although rHPIV1-P(C–) protected against challenge with wt HPIV1, its highly restricted replication in AGMs and in primary human airway epithelial cell cultures suggests that it might be overattenuated for use as a vaccine. Thus, the C proteins of HPIV1 are nonessential but have anti-IFN and antiapoptosis activities required for virulence in primates.

* Corresponding author. Mailing address: LID, NIAID, NIH, Bldg. 50, Room 6511, 50 South Drive MSC 8007, Bethesda, MD 20892-8007. Phone: (301) 594-9029. Fax: (301) 480-1268. E-mail: schmidta{at}niaid.nih.gov

{triangledown} Published ahead of print on 9 July 2008.

{dagger} These authors contributed equally to this study.

Journal of Virology, September 2008, p. 8965-8977, Vol. 82, No. 18
0022-538X/08/$08.00+0     doi:10.1128/JVI.00853-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chambers, R., Takimoto, T. (2009). Host specificity of the anti-interferon and anti-apoptosis activities of parainfluenza virus P/C gene products. J. Gen. Virol. 90: 1906-1915 [Abstract] [Full Text]  
  • Boonyaratanakornkit, J. B., Bartlett, E. J., Amaro-Carambot, E., Collins, P. L., Murphy, B. R., Schmidt, A. C. (2009). The C Proteins of Human Parainfluenza Virus Type 1 (HPIV1) Control the Transcription of a Broad Array of Cellular Genes That Would Otherwise Respond to HPIV1 Infection. J. Virol. 83: 1892-1910 [Abstract] [Full Text]  


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