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Journal of Virology, February 2009, p. 1892-1910, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01373-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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 ^,

Jim B. Boonyaratanakornkit, Emmalene J. Bartlett, Emerito Amaro-Carambot, Peter L. Collins, Brian R. Murphy, and Alexander C. Schmidt^*

Laboratory of Infectious Diseases, Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-8007

Received 1 July 2008/ Accepted 24 November 2008

Human parainfluenza virus type 1 (HPIV1) is an important respiratory pathogen in children and the most common cause of viral croup. We performed a microarray-based analysis of gene expression kinetics to examine how wild-type (wt) HPIV1 infection altered gene expression in human respiratory epithelial cells and what role beta interferon played in this response. We similarly evaluated HPIV1-P(C–), a highly attenuated and apoptosis-inducing virus that does not express any of the four C proteins, and HPIV1-C^F170S, a less attenuated mutant that contains a single point mutation in C and, like wt HPIV1, does not efficiently induce apoptosis, to examine the role of the C proteins in controlling host gene expression. We also used these data to investigate whether the phenotypic differences between the two C mutants could be explained at the transcriptional level. Mutation or deletion of the C proteins of HPIV1 permitted the activation of over 2,000 cellular genes that otherwise would be repressed by HPIV1 infection. Thus, the C proteins profoundly suppress the response of human respiratory cells to HPIV1 infection. Cellular pathways targeted by the HPIV1 C proteins were identified and their transcriptional control was analyzed using bioinformatics. Transcription factor binding sites for IRF and NF-B were overrepresented in some of the C protein-targeted pathways, but other pathways were dominated by less-known factors, such as forkhead transcription factor FOXD1. Surprisingly, the host responses to the P(C–) and C^F170S mutants were very similar, and only subtle differences in the expression kinetics of caspase 3 and TRAIL receptor 2 were observed. Thus, changes in host cell transcription did not reflect the striking phenotypic differences observed between these two viruses.

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* 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

Published ahead of print on 3 December 2008.

Supplemental material for this article may be found at http://jvi.asm.org/.

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Journal of Virology, February 2009, p. 1892-1910, Vol. 83, No. 4
0022-538X/09/$08.00+0     doi:10.1128/JVI.01373-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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