Inhibition of Transcription of the Beta Interferon Gene by the Human Herpesvirus 6 Immediate-Early 1 Protein (original) (raw)
Related papers
Herpes Simplex Virus 1 Has Multiple Mechanisms for Blocking Virus-Induced Interferon Production
Journal of Virology, 2004
In response to viral infection, host cells elicit a number of responses, including the expression of alpha/beta interferon (IFN-alpha/beta). In these cells, IFN regulatory factor-3 (IRF-3) undergoes a sequence of posttranslational modifications that allow it to act as a potent transcriptional coactivator of specific IFN genes, including IFN-beta. We investigated the mechanisms by which herpes simplex virus 1 (HSV-1) inhibits the production of IFN-beta mediated by the IRF-3 signaling pathway. Here, we show that HSV-1 infection can block the accumulation of IFN-beta triggered by Sendai virus (SeV) infection. Our results indicate that HSV-1 infection blocks the nuclear accumulation of activated IRF-3 but does not block the initial virus-induced phosphorylation of IRF-3. The former effect was at least partly mediated by increased turnover of IRF-3 in HSV-1-infected cells. Using mutant viruses, we determined that the immediate-early protein ICP0 was necessary for the inhibition of IRF-3 nuclear accumulation. Expression of ICP0 also had the ability to reduce IFN-beta production induced by SeV infection. ICP0 has been shown previously to play a role in HSV-1 sensitivity to IFN and in the inhibition of antiviral gene production. However, we observed that an ICP0 mutant virus still retained the ability to inhibit the production of IFN-beta. These results argue that HSV-1 has multiple mechanisms to inhibit the production of IFN-beta, providing additional ways in which HSV-1 can block the IFN-mediated host response.
Divergent susceptibilities of human herpesvirus 6 variants to type I interferons
Proceedings of the National Academy of Sciences of the United States of America, 2010
Two distinct human herpesvirus 6 (HHV-6) variants infect humans. HHV-6B is the etiologic agent of roseola and is associated with life-threatening neurological diseases, such as encephalitis, as well as organ transplant failure. The epidemiology and disease association for HHV-6A remain ill-defined. Specific anti-HHV-6 drugs do not exist and classic antiherpes drugs have secondary effects that are often problematic for transplant patients. Clinical trials using IFN were also performed with inconclusive results. We investigated the efficacy of type I IFN (alpha/beta) in controlling HHV-6 infection. We report that cells infected with laboratory strains and primary isolates of HHV-6B are resistant to IFN-alpha/beta antiviral actions as a result of improper IFN-stimulated gene (ISGs) expression. In contrast, HHV-6A-infected cells were responsive to IFN-alpha/beta with pronounced antiviral effects observed. Type II IFN (gamma)-signaling was unaltered in cells infected by either variant. The HHV-6B immediate-early 1 (IE1) physically interacts with STAT2 and sequestrates it to the nucleus. As a consequence, IE1B prevents the binding of ISGF3 to IFN-responsive gene promoters, resulting in ISG silencing. In comparison, HHV-6A and its associated IE1 protein displayed marginal ISG inhibitory activity relative to HHV-6B. The ISG inhibitory domain of IE1B mapped to a 41 amino acid region absent from IE1A. Transfer of this IE1B region resulted in a gain of function that conferred ISG inhibitory activity to IE1A. Our work is unique in demonstrating type I IFN signaling defects in HHV-6B-infected cells and highlights a major biological difference between HHV-6 variants.
Virology, 2003
In the present work we report the cloning of a full-length cDNA encoding the immediate-early (IE) 2 protein from human herpesvirus 6 (HHV-6) variant A (GS strain). The transcript is 4690 nucleotides long and composed of 5 exons. Translation initiation occurs within the third exon and proceeds to the end of U86. Kinetic studies indicate that the 5.5-kb IE2 mRNA is expressed under IE condition, within 2-4 h of infection. IE2 transcripts from both variants A and B are expressed under similar kinetics with IE2 transcripts accumulating up to 96 h postinfection. Although several large transcripts (Ͼ5.5 kb) hybridized with the IE2 probe, suggesting multiple transcription initiation sites, a single form of the IE2 protein, in excess of 200 kDa, was detected by Western blot. Within cells, the IE2 protein was detected (8 -48 h) as intranuclear granules while at later time points (72-120 h), the IE2 protein coalesced into a few large immunoreactive patches. Transfection of cells with an IE2 expression vector (pBK-IE2A) failed to reproduce the patch-like distribution, suggesting that other viral proteins are necessary for this process to occur. Last, IE2 was found to behave as a promiscuous transcriptional activator. Cotransfection experiments in T cells indicate that IE2 can induce the transcription of a complex promoter, such as the HIV-LTR, as well as simpler promoters, whose expression is driven by a unique set of responsive elements (CRE, NFAT, NF-kB). Moreover, minimal promoters having a single TATA box or no defined eukaryotic regulatory elements were significantly activated by IE2, suggesting that IE2 is likely to play an important role in initiating the expression of several HHV-6 genes. In all, the work presented represents the first report on the successful cloning, expression, and functional characterization of the major regulatory IE2 gene/protein of HHV-6.
Nucleic Acids Research, 1983
The structural gene for Herpes simplex virus (HSV) thymidine kinase (Tk) was fused downstream of the 5'-flanking sequence (from-284 to +20;numbering relative to the putative transcription initiation site) of the cloned human interferon-B (IFN-81) gene. The fusion gene was linked to the vectoi pSV2-Ecogpt and the recombinant plasmid was used to transform mouse FM3A cells. All cloned transformants in which the fusion gene was integrated in an intact form produced the Tk specific transcript with the distinct 5' terminus corresponding to that of the authentic IFN-81 mRNA when they were exposed to Newcastle disease virus (NDV). Thus, the results reported here provide evidence for the presence of specific DNA sequences in the 5'-flanking region of the IFN-81 gene required for the virus mediated activation of transcription.
Herpesviruses: interfering innate immunity by targeting viral sensing and interferon pathways
Reviews in medical virology, 2015
Type I-interferon (IFN-I) induction pathway is one of the most commonly stimulated signaling pathways in response to viral infection. During viral infection this pathway is stimulated by various pattern-recognition receptors, which recognize different pathogen-associated molecular patterns. The pathways stimulated by different pattern-recognition receptors merge into common transcription factors IRF3 and IRF7, lead to the production of IFN-I. The secreted IFN-I stimulates JAK-STAT pathway leading to induction of interferon-stimulated genes (ISGs). The ISGs along with IFN-I create antiviral state to eliminate the virus from host. HHV infection enhances IFN-I-mediated innate antiviral response during both de novo infection and lytic reactivation from latency. However, HHV developed various molecular strategies to evade the sudden upsurge of the IFN-I and IFN-I-mediated antiviral response to establish a successful infection. Here, we focus on IFN-I induction and signaling pathways indu...
Journal of Virology, 2006
Mouse hepatitis virus (MHV) does not induce interferon (IFN) production in fibroblasts or bone marrow-derived dendritic cells. In this report, we show that the essential IFN-β transcription factors NF-κB and IFN regulatory factor 3 are not activated for nuclear translocation and gene induction during infection. However, MHV was unable to inhibit the activation of these factors and subsequent IFN-β production induced by poly(I:C). Further, MHV infection did not inhibit IFN-β production mediated by known host pattern recognition receptors (PRRs) (RIG-I, Mda-5, and TLR3). These results are consistent with the notion that double-stranded RNA, produced during MHV infection, is not accessible to cellular PRRs.