Microarray analysis identifies interferon-inducible genes and Stat-1 as major transcriptional targets of human papillomavirus type 31

Human papillomaviruses (HPVs) infect keratinocytes and induce proliferative lesions. In infected cells, viral gene products alter the activities of ce llular proteins, such as Rb and p53, resulting in altered cell cycle respon se. It is likely that HPV gene products also alter expression of cellular g enes. In this study we used microarray analysis to examine the global chang es in gene expression induced by high-risk HPV type 31 (HPV31). Among 7,075 known genes and ESTs (expressed sequence tags) tested, we found that 178 w ere upregulated and 150 were downregulated twofold or more in HPV31 cells c ompared to normal human keratinocytes, While no specific pattern could be d educed from the list of genes that were upregulated, downregulated genes co uld be classified to three groups: genes that are involved in the regulatio n of cell growth, genes that are specifically expressed in keratinocytes, a nd genes whose expression is increased in response to interferon stimulatio n. The basal level of expression of several interferon-responsive genes was found to be downregulated in HPV31 cells by both microarray analysis and N orthern blot analysis in different HPV31 cell lines. When cells were treate d with alpha or gamma interferon, expression of interferon-inducible genes was impaired. At high doses of interferon, the effects were less pronounced . Among the genes repressed by HPV31 was the signal transducer and activato r of transcription (Stat-1), which plays a major role in mediating the inte rferon response. Suppression of Stat-1 expression may contribute to a suppr essed response to interferon as well as immune evasion.