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Journal of Virology, February 2004, p. 1513-1524, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1513-1524.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Virus-Host Cell Interactions during Hepatitis C Virus RNA Replication: Impact of Polyprotein Expression on the Cellular Transcriptome and Cell Cycle Association with Viral RNA Synthesis

Frank Scholle,1,{dagger} Kui Li,1,{dagger} Francis Bodola,1 Masanori Ikeda,1 Bruce A. Luxon,2,3 and Stanley M. Lemon1*

Departments of Microbiology and Immunology,1 Human Biological Chemistry and Genetics,2 Program in Bioinformatics, The University of Texas Medical Branch, Galveston, Texas 77555-10193

Received 27 August 2003/ Accepted 8 October 2003

Considerable controversy surrounds the impact of hepatitis C virus (HCV) protein expression on viability of host cells and regulation of the cell cycle. Both promotion of cellular proliferation and apoptosis have been observed in different experimental systems. To determine whether expression of the entire complement of HCV proteins in the context of ongoing viral RNA replication significantly alters the host cell transcriptome and cell cycle regulatory processes, we carried out high-density oligonucleotide microarray studies and analyzed cell cycle distributions and S-phase entry in Huh7 cell clones harboring selectable, full-length, replicating HCV RNAs that express the entire genotype 1b, HCV-N polyprotein, and clonally related cells in which all viral RNA was eliminated by prior treatment with alpha interferon. Oligonucleotide microarray analyses revealed only subtle, coordinated differences in the mRNA profiles of cells containing replicating viral RNA and their interferon-cured progeny, with variation between different cell clones having a greater influence on the cellular transcriptome than the presence or absence of replicating HCV RNA. Flow cytometric analysis demonstrated no significant differences in cell cycle distribution among populations of asynchronously growing cells of both types. Cell lines containing replicating viral RNA and their interferon-cured progeny were able to reenter the cell cycle similarly after transient G1 arrest. In contrast, although viral protein expression and genome replication did not alter cell cycle control in these cells, HCV genome replication was highly dependent on cellular proliferation, with viral RNA synthesis strongly decreased in poorly proliferating, confluent, or serum-starved cells and substantially enhanced in the S phase of the cell cycle.

* Corresponding author. Mailing address: 5.106 Administration Building, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-0133. Phone: (409) 772-4793. Fax: (409) 772-9798. E-mail: smlemon{at}utmb.edu.

{dagger} F.S. and K.L. contributed equally to this study.

Journal of Virology, February 2004, p. 1513-1524, Vol. 78, No. 3
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.3.1513-1524.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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