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Journal of Virology, January 2006, p. 985-998, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.985-998.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Host Response to the Attenuated Poxvirus Vector NYVAC: Upregulation of Apoptotic Genes and NF-{kappa}B-Responsive Genes in Infected HeLa Cells

Susana Guerra,1 Luis A. López-Fernández,2 Alberto Pascual-Montano,3 José Luis Nájera,1 Angel Zaballos,2 and Mariano Esteban1*

Department of Molecular and Cellular Biology,1 Department of Immunology and Oncology,2 Biocomputing Unit, Centro Nacional de Biotecnología, CSIC, Ciudad Universitaria Cantoblanco, E-28049 Madrid, Spain3

Received 19 August 2005/ Accepted 10 October 2005

NYVAC has been engineered as a safe, attenuated vaccinia virus (VV) vector for use in vaccination against a broad spectrum of pathogens and tumors. Due to the interest in NYVAC-based vectors as vaccines and current phase I/II clinical trials with this vector, there is a need to analyze the human host response to NYVAC infection. Using high-density cDNA microarrays, we found 368 differentially regulated genes after NYVAC infection of HeLa cells. Clustering of the regulated genes identified six discrete gene clusters with altered expression patterns. Clusters 1 to 3 represented 47.5% of the regulated genes, with three patterns of gene activation kinetics, whereas clusters 4 to 6 showed distinct repression kinetics. Quantitative real-time reverse transcription-PCR analysis of selected genes validated the array data. Upregulated transcripts correlated with genes implicated in immune responses, including those encoding interleukin-1 receptor 2 (IL-1R2), IL-6, ISG-15, CD-80, and TNFSF7. NYVAC upregulated several intermediates of apoptotic cascades, including caspase-9, correlating with its ability to induce apoptosis. NYVAC infection also stimulated the expression of NF-{kappa}B1 and NF-{kappa}B2 as well as that of NF-{kappa}B target genes. Expression of the VV host range K1L gene during NYVAC infection prevented NF-{kappa}B activation, but not the induction of apoptosis. This study is the first overall analysis of the transcriptional response of human cells to NYVAC infection and provides a framework for future functional studies to evaluate this vector and its derivatives as human vaccines.

* Corresponding author. Mailing address: Centro Nacional de Biotecnología/CSIC, Ciudad Universitaria Cantoblanco, 28049 Madrid, Spain. Phone: (34) 91/585-4553. Fax: (34) 91/585-4506. E-mail: mesteban{at}cnb.uam.es.

Journal of Virology, January 2006, p. 985-998, Vol. 80, No. 2
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.2.985-998.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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