Herpes Simplex Virus 1 ICP22 but Not U<sub>S</sub>1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

Mostafa, Heba H.; Davido, David J.

doi:10.1128/jvi.02424-13

Cited by 22 publications

(45 citation statements)

References 47 publications

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“…ICP22 is indispensable for virus replication in vivo but not in vitro (34). It is composed of 420 amino acids encoded by the U S 1 gene, and an alternative form, the U S 1.5 gene, is characterized as N-terminally truncated (35). It has been shown that ICP22 interacts with and blocks the recruitment of the positive transcription elongation factor ␤b (P-TEF␤) to viral promoter regions (36).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

Matundan

Ghiasi

2019

J Virol

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Herpes simplex virus type 1 (HSV-1) has the ability to delay its clearance from the eye during ocular infection. Here, we show that ocular infection of mice with HSV-1 suppressed expression of the costimulatory molecule CD80 but not CD86 in the cornea. The presence of neutralizing anti-HSV-1 antibodies did not alleviate this suppression. At the cellular level, HSV-1 consistently downregulated the expression of CD80 by dendritic cells (DCs) but not by other antigen-presenting cells. Furthermore, flow cytometric analysis of HSV-1-infected corneal cells during a 7-day period reduced CD80 expression in DCs but not in B cells, macrophages, or monocytes. This suppression was associated with the presence of virus. Similar results were obtained using infected or transfected spleen cells or bone marrow-derived DCs. A combination of roscovitine treatment, transfection with immediate early genes (IE), and infection with a recombinant HSV-1 lacking the ICP22 gene shows the importance of ICP22 in downregulation of the CD80 promoter but not the CD86 promoter in vitro and in vivo. At the mechanistic level, we show that the HSV-1 immediate early gene ICP22 binds the CD80 promoter and that this interaction is required for HSV-1-mediated suppression of CD80 expression. Conversely, forced expression of CD80 by ocular infection of mice with a recombinant HSV-1 exacerbated corneal scarring in infected mice. Taken together, these studies identify ICP22-mediated suppression of CD80 expression in dendritic cells as central to delayed clearance of the virus and limitation of the cytopathological response to primary infection in the eye. IMPORTANCE HSV-1-induced eye disease is a major public health problem. Eye disease is associated closely with immune responses to the virus and is exacerbated by delayed clearance of the primary infection. The immune system relies on antigen-presenting cells of the innate immune system to activate the T cell response. We found that HSV-1 utilizes a robust and finely targeted mechanism of local immune evasion. It downregulates the expression of the costimulatory molecule CD80 but not CD86 on resident dendritic cells irrespective of the presence of anti-HSV-1 antibodies. The effect is mediated by direct binding of HSV-1 ICP22, the product of an immediate early gene of HSV-1, to the promoter of CD80. This immune evasion mechanism dampens the host immune response and, thus, reduces eye disease in ocularly infected mice. Therefore, ICP22 may be a novel inhibitor of CD80 that could be used to modulate the immune response.

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Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

Matundan

Ghiasi

2019

J Virol

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“…HSV-1 US1 is an IE protein and a multifunctional viral regulator. For example, HSV-1 US1 interacts with RNA polymerase II (83-89) and P-TEFb (90) to regulate viral replication (91). HSV-1 US1 is guanylated, adenylated, and phosphorylated, and at least part of these posttranslational modifications involve the viral protein kinases encoded by UL13 and US3 and casein kinase II (92)(93)(94)(95).…”

Section: Discussionmentioning

confidence: 99%

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Zhang

Liu

Wang

et al. 2015

The Journal of Immunology

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HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217–414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.

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“…Infection with HSV-1 induces the formation of virus-induced chaperone enriched (VICE) domains that can be visualized as distinct foci. VICE domains can be observed in a proportion of (but not all) HSV-1 infected cells, are dependent on the viral proteins ICP22 and ICP27, and form juxtaposed to VRCs [177][178][179][180][181]. Heat shock proteins, as well as other components of the cellular protein quality control machinery including ubiquitin and proteasome sub-units, localize to VICE domains [179,180].…”

Section: Virus-induced Assemblies Proximal To Replication Compartmentsmentioning

confidence: 99%

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

Charman

Weitzman

2020

Viruses

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DNA viruses that replicate in the nucleus encompass a range of ubiquitous and clinically important viruses, from acute pathogens to persistent tumor viruses. These viruses must co-opt nuclear processes for the benefit of the virus, whilst evading host processes that would otherwise attenuate viral replication. Accordingly, DNA viruses induce the formation of membraneless assemblies termed viral replication compartments (VRCs). These compartments facilitate the spatial organization of viral processes and regulate virus-host interactions. Here, we review advances in our understanding of VRCs. We cover their initiation and formation, their function as the sites of viral processes, and aspects of their composition and organization. In doing so, we highlight ongoing and emerging areas of research highly pertinent to our understanding of nuclear-replicating DNA viruses.Viruses 2020, 12, 151 2 of 20 The Initiation and Formation of Replication CompartmentsDNA viruses that replicate in the nucleus exhibit a diverse array of strategies to complete their replication cycle and ultimately produce progeny virions. Despite their many differences, the strategies employed by DNA viruses to initiate productive infection and establish VRCs share many features in common. Indeed, it is likely that all DNA viruses that replicate in the nucleus form VRCs. Following penetration of the host cell and the transport of viral capsids/cores, viral DNA genomes enter the nucleus, where they begin a program of temporally regulated gene expression that initiates productive infection [1,2]. Early gene products include viral proteins required to manipulate the host-cell environment and replicate the viral genome. Viral replication proteins interact with the viral genome and initiate genome replication leading to VRC formation, which is often in concert with certain co-opted host proteins. However, these viruses must overcome several challenges to form VRCs successfully. Firstly, incoming genomes must avoid cellular intrinsic antiviral defenses and homeostatic regulatory pathways such as elements of the DNA damage response (DDR) that respond to the presence of foreign DNA and act to suppress viral gene expression [3][4][5][6][7][8][9][10]. Secondly, VRCs typically form at specific sites within the nucleus, suggesting that viral genomes need to be targeted to these sites in order to initiate VRC formation [6,11,12]. Furthermore, it has been hypothesized that the formation and growth of VRCs may require manipulation of the nuclear environment and the re-organization of host chromatin to overcome the spatial restraints of the nucleus [11][12][13][14][15]. In this section, we review key features of VRC initiation and highlight some major challenges to VRC formation. Interplay between Viral Replication Compartment Formation and Promyelocytic Leukemia Protein Nuclear BodiesA common theme amongst many nuclear-replicating DNA viruses is initiation of VRCs at sites in close proximity to promyelocytic leukemia protein (PML) nuclear bodies (NBs). Since the dis...

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Herpes Simplex Virus 1 ICP22 but Not U_S1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

Cited by 22 publications

References 47 publications

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

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Herpes Simplex Virus 1 ICP22 but Not US1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation

Cited by 22 publications

References 47 publications

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

Herpes Simplex Virus 1 ICP22 Suppresses CD80 Expression by Murine Dendritic Cells

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Replication Compartments of DNA Viruses in the Nucleus: Location, Location, Location

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Herpes Simplex Virus 1 ICP22 but Not U_S1.5 Is Required for Efficient Acute Replication in Mice and VICE Domain Formation