We had earlier discovered that hepatitis C virus (HCV) uses its nonstructural 5A (NS5A) protein to repress the interferon-induced protein kinase, PKR, a primary mediator of the antiviral effects of interferon [8] . Our first application of gene expression profiling to HCV research was therefore to evaluate the effects of interferon treatment on cellular gene expression and to determine whether NS5A was able to alter this pattern of expression [9] . Gary Geiss again headed these studies in which we examined the effects of interferon treatment by using several types of human cells, including HeLa cells, liver cell lines, and primary fetal hepatocytes. In response to interferon, 50 of the approximately 4,600 genes examined were consistently induced in each of these cell types and another 60 were induced in a cell typespecific manner. A search for interferon-stimulated response elements (ISREs) in genomic DNA located upstream of interferon-stimulated genes revealed both previously identified and novel putative ISREs. The expression of NS5A partially blocked the interferon-mediated induction of interferon-stimulated genes and inhibited the induction of a reporter gene driven from an ISRE-containing promoter, further suggesting that NS5A may play a role in HCV resistance to interferon. This study also set the stage for our use of genomics to better understand the interferon response and the varied mechanisms used by viruses to evade the effects of interferon.