Silencing Herpes Simplex Virus Type 1 Capsid Protein Encoding Genes by siRNA: A Promising Antiviral Therapeutic Approach

Jin, Fujun; Shen, Li; Zheng, Kai; Zhuo, Cuiqin; Ma, Kaiqi; Chen, Maoyun; Wang, Qiaoli; Zhang, Pei-Zhuo; Fan, Jianglin; Ren, Zhe; Wang, Yifei

doi:10.1371/journal.pone.0096623

Cited by 24 publications

(22 citation statements)

References 50 publications

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“…The mice were then infected with HSV-1 and the livers were harvested 5 days post infection. Consistent with a previous report 45 , the knockdown of capsid protein VP23 (UL18) suppressed the level of viral mRNA (Fig. 8a, lane 2).…”

Section: Nop53 Knockdown Reduces Hsv-1/f Growth and Pathogenesis In Micesupporting

confidence: 92%

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Meng

Han

et al. 2018

Cell Death Dis

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To ensure efficient virus replication, herpes simplex virus type 1 (HSV-1) encodes several viral proteins to counter host defense response upon infection. Among these proteins, the multifunctional viral protein γ34.5 crucially interferes with or disrupts several antiviral pathways at multiple levels. The current study shows that γ34.5 utilizes nucleolar protein NOP53 to facilitate the dephosphorylation of eukaryotic initiation factor eIF2α for efficient viral translation. Our study shows that: (1) ectopic expression of NOP53 greatly increases the intracellular and extracellular viral yields of HSV-1 (wild strain F) in type I interferon-deficient Vero cells, and more subtly promotes viral replication of γ34.5 deletion mutant virus HSV-1/Δγ34.5. (2) NOP53 is migrated from nuclei in HSV-1/F infected cells, but is redistributed incompletely after infection by either HSV-1/Δγ34.5 or ICP4 deletion mutant virus HSV-1/d120 (replication inadequate). Ectopic expression of γ34.5, consequently, induces cytoplasmic translocation of NOP53 in response to HSV-1/Δγ34.5 infection. (3) Increase of NOP53, in two forms of transient transfection and in vitro expression, attenuates the phosphorylation level of eIF2α in HSV-1/F infected cells, but fails to affect eIF2α phosphorylation induced by HSV-1/Δγ34.5 infection. (4) Knockdown of NOP53, which impairs the specific interaction between γ34.5 and protein phosphatase PP1α, disrupts the ability of γ34.5 to maintain HSV-1 virulence. (5) NOP53 knockdown also significantly reduces tissue damage and decreases viral yield in livers of HSV-1 infected mice. Our findings expand the understanding of the underlying mechanism by which viral protein γ34.5 induces NOP53 redistribution; cytoplasmic NOP53 facilitates γ34.5 recruitment of PP1α to dephosphorylate eIF2α, for optimal viral replication. This paper also demonstrates that blocking the specific interaction between γ34.5 and PP1α would be a useful approach for the development of antiviral agents.

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Section: Nop53 Knockdown Reduces Hsv-1/f Growth and Pathogenesis In Micesupporting

confidence: 92%

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Meng

Han

et al. 2018

Cell Death Dis

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“…ACV mainly acts as a substrate of HSV Thymidine kinase (TK) and inhibits viral DNA replication, and ACV-resistant HSV clinical isolates are TK-negative, TK-low-producer mutants, and TK-altered mutants [34]. In this study, we also assessed whether amentoflavone had antiviral activity against ACV-resistant strains, including HSV-1/Blue, a TK mutant derived from HSV-1, and two clinical HSV-1 strains HSV-1/106 and HSV-1/153 [35]. As shown in Figure 3A, no antiviral activity of ACV toward those viruses was observed even at a high concentration (50 μM).…”

Section: Resultsmentioning

confidence: 99%

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

Song

et al. 2019

Viruses

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Infection of Herpes simplex virus 1 (HSV-1) induces severe clinical disorders, such as herpes simplex encephalitis and keratitis. Acyclovir (ACV) is the current therapeutic drug against viral infection and ACV-resistant strains have gradually emerged, leading to the requirement for novel antiviral agents. In this study, we exhibited the antiviral activity of amentoflavone, a naturally occurring biflavonoid, toward HSV-1 and ACV-resistant strains. Amentoflavone significantly inhibited infection of HSV-1 (F strain), as well as several ACV-resistant strains including HSV-1/106, HSV-1/153 and HSV-1/Blue at high concentrations. Time-of-drug-addition assay further revealed that amentoflavone mainly impaired HSV-1 early infection. More detailed study demonstrated that amentoflavone affected cofilin-mediated F-actin reorganization and reduced the intracellular transportation of HSV-1 from the cell membrane to the nucleus. In addition, amentoflavone substantially decreased transcription of viral immediate early genes. Collectively, amentoflavone showed strong antiviral activity against HSV-1 and ACV-resistant strains, and amentoflavone could be a promising therapeutic candidate for HSV-1 pathogenesis.

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“…When shell maturation is accompanied by genome encapsidation, the resulting product is a C capsid, or nucleocapsid. This critical process is a target for antiviral development (52)(53)(54)(55)(56)(57)(58)(59)(60), which is bolstered by ongoing refinements of cryo-EM reconstruction techniques that have led to herpesvirus capsid models with near-atomic resolution (19,(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

The Apical Region of the Herpes Simplex Virus Major Capsid Protein Promotes Capsid Maturation

Ruhge

Huet

Conway

et al. 2018

J Virol

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The herpesvirus capsid assembles in the nucleus as an immature procapsid precursor built around viral scaffold proteins. The event that initiates procapsid maturation is unknown, but it is dependent upon activation of the VP24 internal protease. Scaffold cleavage triggers angularization of the shell and its decoration with the VP26 and pUL25 capsid-surface proteins. In both the procapsid and mature angularized capsid, the apical region of the major capsid protein (VP5) is surface exposed. We investigated whether the VP5 apical region contributes to intracellular transport dynamics following entry into primary sensory neurons and also tested the hypothesis that conserved negatively charged amino acids in the apical region contribute to VP26 acquisition. To our surprise, neither hypothesis proved true. Instead, mutation of glutamic acid residues in the apical region delayed viral propagation and induced focal capsid accumulations in nuclei. Examination of capsid morphogenesis based on epitope unmasking, capsid composition, and ultrastructural analysis indicated that these clusters consisted of procapsids. The results demonstrate that, in addition to established events that occur inside the capsid, the exterior capsid shell promotes capsid morphogenesis and maturation. Herpesviruses assemble capsids and encapsidate their genomes by a process that is unlike those of other mammalian viruses but is similar to those of some bacteriophage. Many important aspects of herpesvirus morphogenesis remain enigmatic, including how the capsid shell matures into a stable angularized configuration. Capsid maturation is triggered by activation of a protease that cleaves an internal protein scaffold. We report on the fortuitous discovery that a region of the major capsid protein that is exposed on the outer surface of the capsid also contributes to capsid maturation, demonstrating that the morphogenesis of the capsid shell from its procapsid precursor to the mature angularized form is dependent upon internal and external components of the megastructure.

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Silencing Herpes Simplex Virus Type 1 Capsid Protein Encoding Genes by siRNA: A Promising Antiviral Therapeutic Approach

Cited by 24 publications

References 50 publications

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Multifunctional viral protein γ34.5 manipulates nucleolar protein NOP53 for optimal viral replication of HSV-1

Amentoflavone Inhibits HSV-1 and ACV-Resistant Strain Infection by Suppressing Viral Early Infection

The Apical Region of the Herpes Simplex Virus Major Capsid Protein Promotes Capsid Maturation

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