Modulation of Human Herpesvirus 8/Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Activator Transactivation by Interferon Regulatory Factor 7

Abstract

Human herpesvirus 8 (HHV-8)/Kaposi's sarcoma-associated herpesvirus infection goes through lytic and latent phases that are regulated by viral gene products, but very little is known about the involvement of host proteins. The replication and transcription activator (RTA) is a viral protein sufficient to initiate lytic replication by activating downstream genes, including the viral early gene open reading frame 57 (ORF 57), which codes for a posttranscriptional activator. In this study, we demonstrate that cellular interferon regulatory factor 7 (IRF-7) negatively regulates this process by competing with RTA for binding to the RTA response element in the ORF 57 promoter to down-regulate RTA-induced gene expression. We also show that alpha interferon represses RTA-mediated transactivation and that repression involves IRF-7. Our study indicates that upon HHV-8 infection, the host responds by suppression of lytic gene expression through binding of IRF-7 to the lytic viral gene promoter. These findings suggest that HHV-8 has developed a novel mechanism to induce but then subvert the innate antiviral response, specifically the interferon-signaling pathway, to regulate RTA activity and ultimately the viral latent/lytic replicative cycle.

Hepatitis C Virus Inhibits Intracellular Interferon Alpha Expression in Human Hepatic Cell Lines *

“…42,50 In conclusion, our study demonstrating that HCV has the ability to undermine intracellular innate immunity of the host cells provides a plausible mechanism responsible for HCV persistence in the hepatic cells. Our data, in conjunction with the reports by Foy et al 3 and Wang et al, 39 suggest that HCV not only interferes with the IRF-3-mediated early protein pathway of type I IFNs, but also inhibits IRF-7-mediated IFN-␣ activation in the hepatic cells. Thus, HCV uses complex mechanisms to target multiple steps of the type I IFN signaling pathway in the hepatic cells, which results in significant suppression of endogenous IFN-␣, a critical self-defense weapon used by the hepatic cells.…”

“…This speculation is supported by a recent report that IRF-7 can directly inhibit human herpesvirus 8 (HHV-8) replication. 39 These data support the possibility that other anti-HCV factor(s) induced by IRF-7 also play a role in the observed HCV replicon inhibition. These findings indicated that endogenous IFN-␣ indeed has a critical role in controlling HCV replication in the hepatic cells.…”

Kaposi's Sarcoma-Associated Herpesvirus Rta Tetramers Make High-Affinity Interactions with Repetitive DNA Elements in the Mta Promoter To Stimulate DNA Binding of RBP-Jk/CSL

“…The 4th unit of the A/T repeat has also been shown to be part of a binding site for IRF7, which represses Rta transactivation of the Mta promoter (41).…”

Alpha/Beta Interferons Regulate Murine Gammaherpesvirus Latent Gene Expression and Reactivation from Latency

“…A subset of these vIRFs are expressed during viral latency, suggesting that IFN-␣/␤ exerts antiviral effects on latent cells, thereby leading to selective pressure to maintain vIRF expression (9,31,65,102). Surprisingly, vIRF3 stimulates the transcriptional induction of the cellular IRF-7 (51), and KSHV maintains sequences in at least one key lytic promoter that binds cellular IRF-7, resulting in the inhibition of viral replication in the presence of an IFN-␣/␤ response (88). In addition, the promoter for the KSHV viral interleukin 6 (vIL-6) gene is transactivated by IFN-␣/␤, and its upregulation restores IL-6 autocrine growth signals lost when IFN-␣/␤ downregulates cellular IL-6 (13,63).…”