Evidence that the Immediate-Early Gene Product ICP4 Is Necessary for the Genome of the Herpes Simplex Virus Type 1 ICP4 Deletion Mutant Strain
            <i>d</i>
            120 To Circularize in Infected Cells

Su, Ying‐Hsiu; Zhang, Xianchao; Wang, Xiaohe; Fraser, Nigel W.; Block, Timothy M.

doi:10.1128/jvi.01869-06

Cited by 15 publications

(18 citation statements)

References 35 publications

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“…1A) were examined. Relative to VP5, levels of ICP4 similar to those of wild type KOS virions were found associated with d 120 virions and a ∼ 40 kiloDalton ICP4 fragment was detected as reported previously [25]. To begin to address whether ICP4 is present in d 120 virion preparations as a cellular contaminant due to ICP4 overexpression by the E5 cells, we probed for the host cell protein Rab7.…”

Section: Resultssupporting

confidence: 62%

Analysis of Herpes Simplex Virion Tegument ICP4 Derived from Infected Cells and ICP4-Expressing Cells

2013

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ICP4 is the major transcriptional regulatory protein of herpes simplex virus (HSV). It is expressed in infected cells with immediate early kinetics and is essential for viral growth. ICP4 is also a structural component of the virion tegument layer. Herpesviral tegument proteins exert regulatory functions important for takeover of the host cell. Tegument ICP4 has not been well characterized. We examined the ICP4 present in HSV-1 virions that were either derived from wild type infected cells or from ICP4-expressing (E5) cells infected with ICP4 deletion virus d120. Limited proteolysis demonstrated that virion-associated ICP4 from particles derived from E5 cells was indeed an internal component of the virion. A similar subset of virion structural proteins was detected in viral particles regardless of the cellular origin of ICP4. Genotypically ICP4-negative virions complemented with tegument ICP4 entered cells via a proteasome-dependent, pH-dependent pathway similar to wild type virions. In infected cells, ICP4 was distributed predominantly in intranuclear replication compartments regardless of whether it was expressed from a transgene or from the HSV genome.

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Section: Resultssupporting

confidence: 62%

Analysis of Herpes Simplex Virion Tegument ICP4 Derived from Infected Cells and ICP4-Expressing Cells

2013

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“…The expression of full-length ICP4 protein by d120-infected and not mock-infected E5 cells is consistent with other reports 23. E5 cells contain a stably transfected ICP4 gene under the control of its endogenous promoter 11.…”

Section: Resultssupporting

confidence: 91%

Development of an oncolytic herpes simplex virus using a tumor-specific HIF-responsive promoter

et al. 2010

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We exploited the differential activation of hypoxia-inducible factor (HIF)-dependent gene expression in tumors versus normal tissue for the design of a targeted oncolytic Herpes simplex virus type-1 (HSV-1). A gene that is essential for viral replication, ICP4, was placed under the regulation of a HIF-responsive promoter and then introduced into the thymidine kinase locus (UL23) of HSV d120 which contains partial deletions in the two endogenous ICP4 genes. Recombinant HIF-HSV were isolated and their derivation from d120 was verified by expression of a truncated, nonfunctional form of ICP4 protein. Disruption of the UL23 locus was confirmed by loss of thymidine kinase expression and resistance to acyclovir. Unexpectedly, HIF-HSV expressed ICP4 and induced tumor cell lysis at similar levels under normoxia and hypoxia. The lack of HIF-dependent ICP4 transgene expression by HIF-HSV was due to two factors that have not previously been reported- reversion of the ICP4 gene region to its wild-type configuration and increased HIF-transcriptional activity under normoxia when cells were infected with any strain of HSV-1. The findings that an oncolytic HSV-1 is genetically unstable and can activate a tumor-related promoter in a non-specific manner have important implications for any proposed use of this virus in cancer therapy.

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“…However, the same may not be true during infection of other cell types or in natural human infections. Interestingly, recent data suggest that the virionlocalized ICP4 plays a role in genome circularization early in infection (55). Furthermore, as both ICP0 and ICP4 are powerful transcriptional activators, one could envision that virionassociated ICP0/4 could help stimulate viral gene expression at the very earliest stages of infection.…”

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confidence: 99%

Herpes Simplex Virus Type 1 Immediate-Early Protein ICP27 Is Required for Efficient Incorporation of ICP0 and ICP4 into Virions

Sedlačková

Rice

2008

J Virol

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Early in infection, herpes simplex virus type 1 (HSV-1) immediate-early (IE) proteins ICP0 and ICP4 localize to the nucleus, where they stimulate viral transcription. Later in infection, ICP0 and to a lesser extent ICP4 accumulate in the cytoplasm, but their biological role there is unknown. Previously, it was shown that the cytoplasmic localization of ICP0/4 requires the multifunctional IE protein ICP27, which is itself an activator of viral gene expression. Here, we identify a viral ICP27 mutant, d3-4, which is unable to efficiently localize ICP0 and ICP4 to the cytoplasm but which otherwise resembles wild-type HSV-1 in its growth and viral gene expression phenotypes. These results genetically separate the function of ICP27 that affects ICP0/4 localization from its other functions, which affect viral growth and gene expression. As both ICP0 and ICP4 are known to be minor virion components, we used d3-4 to test the hypothesis that the cytoplasmic localization of these proteins is required for their incorporation into viral particles. Consistent with this conjecture, d3-4 virions were found to lack ICP0 in their tegument and to have greatly reduced levels of ICP4. Thus, the cytoplasmic localization of ICP0 and ICP4 appears to be a prerequisite for the assembly of these important transcriptional regulatory proteins into viral particles. Furthermore, our results show that ICP27 plays a previously unrecognized role in determining the composition of HSV-1 virions.Viral proteins that are present in the cell at the very earliest stages of infection can have critical regulatory functions, e.g., to counteract host immunity or to transactivate viral gene expression. For herpes simplex virus type 1 (HSV-1), there are two categories of viral regulatory polypeptides which are present very early in infection: those which enter the cell as components of the virion tegument and those which are expressed immediately upon infection as immediate-early (IE) proteins. Interestingly, two HSV-1 proteins, ICP0 and ICP4, fall into both categories, as they are abundantly expressed IE proteins as well as minor components of the tegument layer of virions (12,64,65).The virions of HSV-1 and other herpesviruses are among the most complex viral particles known, consisting of more than 30 viral proteins as well as some cellular components (36). HSV-1 virions are composed of four morphologically distinct structures: core, capsid, tegument, and envelope. The inner nucleoprotein core containing the 152-kbp viral double-stranded DNA genome is enclosed in a capsid which is surrounded by a proteinaceous layer known as the tegument, which in turn is enclosed in a host cell-derived lipid envelope containing numerous viral glycoproteins. The tegument (reviewed in reference 34) consists of more than 15 proteins, several of which are known to have regulatory roles in the newly infected cell. It interacts with the capsid on one side and the cytoplasmic tails of envelope glycoproteins on the other to secure the integrity of the virus particle. Although th...

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Evidence that the Immediate-Early Gene Product ICP4 Is Necessary for the Genome of the Herpes Simplex Virus Type 1 ICP4 Deletion Mutant Strain d 120 To Circularize in Infected Cells

Cited by 15 publications

References 35 publications

Analysis of Herpes Simplex Virion Tegument ICP4 Derived from Infected Cells and ICP4-Expressing Cells

Analysis of Herpes Simplex Virion Tegument ICP4 Derived from Infected Cells and ICP4-Expressing Cells

Development of an oncolytic herpes simplex virus using a tumor-specific HIF-responsive promoter

Herpes Simplex Virus Type 1 Immediate-Early Protein ICP27 Is Required for Efficient Incorporation of ICP0 and ICP4 into Virions

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