Inhibition of host cell immune responses by the Epstein-Barr virus immediate-early protein BZLF1

To eliminate invading pathogens, the host's immune system employs a variety of strategies. Viruses have evolved elaborate mechanisms to circumvent many aspects of host immunity. In the studies presented here, we investigated the role of the Epstein-Barr virus immediate-early proteins, BZLF1 and BRLF1, in protection of cells from anti-viral responses.; Interferons play a central role in resistance to viral infection. We found that BZLF1 expression inhibits the IFN-gamma signaling pathway. BZLF1 inhibited the induction of important downstream target genes, such as IRF-1 and MHC class II, as well upstream signaling events. These effects were due to decreased expression of the IFN-gamma receptor in BZLF1-expressing cells.; Tumor necrosis factor-alpha (TNF-alpha) induces genes that function in immune and inflammatory responses. Additionally, TNF-alpha plays a role in host defense by induction of cellular apoptosis. BZLF1 expression prevented TNF-alpha activation of target genes and inhibited TNF-alpha-induced cell death. We found that BZLF1 downregulates the promoter for TNF-R1, thus eliminating expression of the cellular receptor for TNF-alpha.; The NF-kappaB pathway is utilized by the immune system to initiate an immediate cellular response to a wide range of stimuli. BZLF1 interacts with, and is inhibited by, the NF-kappaB family member p65. In these studies, we show that BZLF1 inhibits p65 dependent gene expression. Surprisingly, BZLF1 increased the amount of nuclear NF-kappaB. In spite of this BZLF1-associated increase in nuclear NF-kappaB, BZLF1 did not induce binding of NF-kappaB to responsive promoters, including the IkappaB-alpha promoter, in vivo. Instead, BZLF1 decreased expression of IkappaB-alpha. Overexpression of p65 dramatically inhibited the lytic replication cycle of EBV, confirming that NF-kappaB inhibits BZLF1 transcriptional function. These findings are consistent with a model in which BZLF1 inhibits the transcriptional function of p65, resulting in decreased expression of IkappaB-alpha, and subsequent nuclear translocation of NF-kappaB. This nuclear translocation of NF-kappaB may promote viral latency by negatively regulating BZLF1 transcriptional activity. In situations where p65 activity is limiting in comparison to BZLF1, the ability of BZLF1 to inhibit p65 transcriptional function may protect the virus from anti-viral responses.; These studies suggest that BZLF1 may play an important role in protecting EBV infected cells from host immune responses.