Herpes Simplex Virus 1 Has Multiple Mechanisms for Blocking Virus-Induced Interferon Production (original) (raw)
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Virology, 2002
Herpes simplex virus type 1 (HSV-1) is resistant to the antiviral effects of interferon (IFN)-alpha, -beta, or -gamma. The fact that ICP0(-) mutants replicate like wild-type virus in IFN-alpha/beta receptor knockout mice (Leib et al., 1999, J. Exp. Med. 189, 663) suggested that ICP0 may serve a direct role in the resistance of HSV-1 to IFN. To test this hypothesis, the effects of IFN-alpha, -beta, and -gamma were compared against wild-type HSV-1 and an ICP0(-) mutant virus, 7134. In Vero cells, 7134 was more sensitive to inhibition by low doses of type I IFN (-alpha/beta) or type II IFN (-gamma) than vesicular stomatitis virus, a well-studied IFN-sensitive virus. At a concentration of 100 U/ml, IFN-alpha, -beta, or -gamma reduced the efficiency of 7134 plaque formation by 120-, 560-, and 45-fold, respectively. In contrast, none of the IFNs reduced wild-type HSV-1 plaque formation by more than 3-fold. Even when Vero cells were infected with 10 pfu per cell, IFN-alpha and -beta inhibited 7134 replication by over 100-fold, but inhibition by IFN-gamma decreased to less than 10-fold. While IFN-beta efficiently inhibited 7134 replication in primary mouse kidney and SK-N-SH cells, IFN-gamma did not inhibit 7134 to a comparable extent in these cells. ICP0 provided in trans from an adenovirus vector allowed 7134 to replicate efficiently in Vero cells in the presence of IFN-alpha, -beta, or -gamma. While IFN-beta or -gamma efficiently repressed the ICP0 promoter-lacZ reporter gene in 7134 (i.e., approximately 60-fold reduction in beta-galactosidase activity), ICP0 provided in trans almost completely reversed IFN-mediated repression of the lacZ gene in 7134. The results suggest that the rate of ICP0 expression in infected cells in vivo may be critical in determining whether host IFNs repress the HSV-1 genome. This concept is discussed in light of its potential relevance to the establishment of latent HSV-1 infections.
Role of IFN-α/β signaling in the prevention of genital herpes virus type 2 infection
Journal of Reproductive Immunology, 2007
Genital herpes, caused by herpes simplex virus type 2 (HSV-2), is the most common genital ulcer disease worldwide. HSV-2 infection causes a variety of symptoms, ranging from subclinical/silent infection to severe and recurrent episodes of genital blisters and ulcers, and the virus can also in rare cases cause meningitis. In primary infection, the virus sequentially enters and replicates in epithelial cells followed by local sensory neurons. In the latter, a lifelong infection is established via the induction of viral latency or dormancy. Latent virus is however continuously reactivated, also in those with a silent infection, which results in a low-grade viral replication and shedding into the vaginal lumen. This reactivation can in many individuals be amplified following e.g. stress, hormonal variations or immune suppression, which results in recurrent genital disease. Cell-mediated immunity and interferons (IFN) are probably the most efficient immune mediators involved in combating HSV-2. In particular type I IFN (i.e. IFN-α/β) which block protein synthesis and thus viral multiplication, but also NK cells which destroy HSV-2-infected cells, play major roles in limiting the HSV-2 replication during the first days of infection. Then, once the sophisticated acquired immune response has had sufficient time to mature and expand, IFN-γ-producing and cytolytic CD4+ and CD8+ T cells appear, and these cells are instrumental in clearing the mucosal infection and probably also in later containment of latent virus. The activation/induction of NK cells, T cells and IFN is tightly regulated and relies on an intricate network of membrane-bound and intracellular signaling systems. In this thesis I have investigated how a few selected signaling mediators or pathways affect HSV-2 immunity. One of these mediators, the transcription factor T-box expressed in T cells (Tbet), turned out to be particularly interesting as it influenced the function of both NKcells and T-cells as well as the production of IFN. Because of its impact on such crucial components of the anti-HSV-2 innate and acquired immune response, I have chosen to focus my thesis framework on the transcription factor T-bet.
Virology, 2010
Host cells respond to viral infection by the production of type I interferons (IFNs), which induce the expression of antiviral genes. Herpes simplex virus I (HSV-1) encodes many mechanisms that inhibit the type I IFN response, including the ICP27-dependent inhibition of type I IFN signaling. Here we show inhibition of Stat-1 nuclear accumulation in cells that express ICP27. ICP27 expression also induces the secretion of a small, heat-stable type I IFN antagonizing protein that inhibits Stat-1 nuclear accumulation. We show that the inhibition of IFN-induced Stat-1 phosphorylation occurs at or upstream of Jak-1 phosphorylation. Finally, we show that ISG15 expression is induced after IFNα treatment in mock-infected cells, but not cells infected with WT HSV-1 or ICP27 − HSV-1. These data suggest that HSV-1 has evolved multiple mechanisms to inhibit IFN signaling not only in infected cells, but also in neighboring cells, thereby allowing for increased viral replication and spread.
Functional Genomic Analysis of Herpes Simplex Virus Type 1 Counteraction of the Host Innate Response
Journal of Virology, 2006
Herpes simplex virus type 1 (HSV-1) mutants lacking the ICP34.5 gene are severely attenuated in mouse models and have a significant growth defect in confluent mouse embryo fibroblasts. Previously, ICP34.5 was demonstrated to have a crucial role in evading the innate immune response to infection by mediating the dephosphorylation of eIF2␣, a translation initiation factor phosphorylated by PKR during the antiviral response. To further understand the role of ICP34.5 in evasion of the antiviral response, we used transcriptional profiling to examine host cell gene expression in both wild-type and ICP34.
Journal of Virology, 2002
In vivo evidence suggests that T-cell-derived gamma interferon (IFN-gamma) can directly inhibit the replication of herpes simplex virus type 1 (HSV-1). However, IFN-gamma is a weak inhibitor of HSV-1 replication in vitro. We have found that IFN-gamma synergizes with the innate IFNs (IFN-alpha and -beta) to potently inhibit HSV-1 replication in vitro and in vivo. Treatment of Vero cells with either IFN-beta or IFN-gamma inhibits HSV-1 replication by <20-fold, whereas treatment with both IFN-beta and IFN-gamma inhibits HSV-1 replication by approximately 1,000-fold. Treatment with IFN-beta and IFN-gamma does not prevent HSV-1 entry into Vero cells, and the inhibitory effect can be overcome by increasing the multiplicity of HSV-1 infection. The capacity of IFN-beta and IFN-gamma to synergistically inhibit HSV-1 replication is not virus strain specific and has been observed in three different cell types. For two of the three virus strains tested, IFN-beta and IFN-gamma inhibit HSV-1 replication with a potency that approaches that achieved by a high dose of acyclovir. Pretreatment of mouse eyes with IFN-beta and IFN-gamma reduces HSV-1 replication to nearly undetectable levels, prevents the development of disease, and reduces the latent HSV-1 genome load per trigeminal ganglion by approximately 200-fold. Thus, simultaneous activation of IFN-alpha/beta receptors and IFN-gamma receptors appears to render cells highly resistant to the replication of HSV-1. Because IFN-alpha or IFN-beta is produced by most cells as an innate response to virus infection, the results imply that IFN-gamma secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo.
Role for herpes simplex virus 1 ICP27 in the inhibition of type I interferon signaling
Virology, 2008
Host cells respond to viral infection by many mechanisms, including the production of type I interferons which act in a paracrine and autocrine manner to induce the expression of antiviral interferon-stimulated genes (ISGs). Viruses have evolved means to inhibit interferon signaling to avoid induction of the innate immune response. Herpes simplex virus 1 (HSV-1) has several mechanisms to inhibit type I interferon production, the activities of ISGs, and the interferon signaling pathway itself. We report that the inhibition of the Jak/STAT pathway by HSV-1 requires viral gene expression and that viral immediate-early protein ICP27 plays a role in downregulating STAT-1 phosphorylation and in preventing the accumulation of STAT-1 in the nucleus. We also show that expression of ICP27 by transfection causes an inhibition of IFN-induced STAT-1 nuclear accumulation. Therefore, ICP27 is necessary and sufficient for at least some of the effects of HSV infection on STAT-1.
Journal of Virology, 2007
Human herpesviruses (HHV) are stealth pathogens possessing several decoy or immune system evasion mechanisms favoring their persistence within the infected host. Of these viruses, HHV-6 is among the most successful human parasites, establishing lifelong infections in nearly 100% of individuals around the world. To better understand this host-pathogen relationship, we determined whether HHV-6 could interfere with the development of the innate antiviral response by affecting interferon (IFN) biosynthesis. Using inducible cell lines and transient transfection assays, we have identified the immediate-early 1 (IE1) protein as a potent inhibitor of IFN- gene expression. IE1 proteins from both HHV-6 variants were capable of suppressing IFN- gene induction.
Journal of Virology, 2002
Alpha/beta interferons (IFN-␣/) are potent, endogenous antiviral cytokines that suppress the replication of RNA and DNA viruses, including herpes simplex virus type 1 (HSV-1). The present study compared the efficacies of IFN-␣/ transgenes, including IFN-␣1, -␣4, -␣5, -␣6, -␣9, and -, against HSV-1 infection. L929 cells transfected with the IFN-␣/ transgenes produced similar levels of IFN, as measured by bioassay and enzyme-linked immunosorbent assay. In addition, transfected cells were less susceptible to HSV-1 infection than were cells transfected with a plasmid vector control. The murine IFN- plasmid construct exhibited the greatest reduction, while the murine IFN-␣5 transgene showed a modest inhibitory effect in viral titers recovered from the supernatants of transfected, infected L929 cultures. Consistent with this observation, the IFN- transgene antagonized viral transcript levels, including infected cell protein 27, thymidine kinase, and glycoprotein B, to a greater extent than did the IFN-␣ transgenes at 6 to 10 h postinfection as determined by real-time PCR. Cells transfected with the IFN-␣4, IFN-␣9, or IFN- transgenes showed the greatest reduction in viral protein expression relative to the other transfected cells, which was associated with increased STAT1 expression. The absence of the IFN-responsive protein kinase R (PKR) gene completely abrogated the antiviral induction by all IFN-␣/ against HSV-1. In the absence of RNase L, viral yields were increased 10-fold, but the antiviral effect of IFN was either unaffected or enhanced. These results suggest that the predominant IFNmediated, antiviral pathway during HSV-1 infection taken by IFN-␣/ in L929 cells utilizes PKR.
The EMBO journal, 2016
Herpes simplex virus (HSV) 1 stimulates type I IFN expression through the cGAS-STING-TBK1 signaling axis. Macrophages have recently been proposed to be an essential source of IFN during viral infection. However, it is not known how HSV-1 inhibits IFN expression in this cell type. Here, we show that HSV-1 inhibits type I IFN induction through the cGAS-STING-TBK1 pathway in human macrophages, in a manner dependent on the conserved herpesvirus protein ICP27. This viral protein was expressed de novo in macrophages with early nuclear localization followed by later translocation to the cytoplasm where ICP27 prevented activation of IRF3. ICP27 interacted with TBK1 and STING in a manner that was dependent on TBK1 activity and the RGG motif in ICP27. Thus, HSV-1 inhibits expression of type I IFN in human macrophages through ICP27-dependent targeting of the TBK1-activated STING signalsome.