B virus (Cercopithecine herpesvirus 1) is an alphaherpesvirus indigenous to macaque monkeys and is closely related to herpes simplex virus type 1 (HSV-1). Disease caused by B virus, which is often mild or asymptomatic in its natural host, the macaque monkey, is similar in infected macaques to HSV-1 infection in humans. When B virus zoonotically infects foreign hosts, e.g., humans, high morbidity and mortality are evidenced in > 80% of untreated cases. To explore the underlying reasons for differences in pathogenesis between B virus and HSV-1 infection in humans, human microarrays were used to comparatively examine global cellular gene expression patterns engaged as a result of infection of human foreskin fibroblasts (HFFs). Our results demonstrate that these closely related simplexvirus family members have divergent strategies to thwart host cell pathways related to innate defenses. In these studies, B virus did not induce detectable interferon, cytokine or chemokine genes, in sharp contrast to HSV-1, which induced innate immune responsive genes in infected cells. Although no innate immune response genes were found to be up-regulated by B virus infection, B virus induced I£eB£a, which was the only gene found to be involved in the NF-£eB signaling pathway within the innate immunity biological network. Quantification of NF-£eB p50 DNA binding activity in virus-infected nuclear extracts demonstrated that NF-£eB p50 DNA binding activity was lower in B virus-infected cells. Suppression of I£eB£a in B virus infected cells by siRNA restored NF-£eB-induced cytokine and chemokine expressions. Data presented here support the model that I£eB£a inhibits NF-£eB regulated immune responsive genes in B virus-infected HFF cells, and this response differs from that observed in HFF cells infected with HSV-1. The result is that B virus alters the NF-£eB regulated expression of cytokine and chemokine genes of HFF cells differently from HSV-1 early after infection. These differences in cytokine and chemokine expression may be associated with the delayed or reduced host responses observed in B virus infected humans and underlie the failure of adaptive responses in zoonotically infected humans.