Efficient Activation of Viral Genomes by Levels of Herpes Simplex Virus ICP0 Insufficient To Affect Cellular Gene Expression or Cell Survival

Hobbs, William E.; Brough, Douglas E.; Kovesdi, Imre; DeLuca, Neal A.

doi:10.1128/jvi.75.7.3391-3403.2001

Cited by 47 publications

(70 citation statements)

References 58 publications

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“…Quiescent infection was achieved by using an HSV-1 mutant, d109, which does not express the five HSV IE proteins and contains an enhanced GFP (EGFP) transgene under control of the human cytomegalovirus IE promoter (17). In cultured cells, d109 establishes a persistent and quiescent state, in which EGFP expression is largely repressed, but can be activated by providing ICP0, in trans (17,18). These characteristics are similar to events that occur during latency and reactivation from latency.…”

mentioning

confidence: 67%

Relationship of herpes simplex virus genome configuration to productive and persistent infections

Jackson

DeLuca

2003

Proc. Natl. Acad. Sci. U.S.A.

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119

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Infection of susceptible cells by herpes simplex virus (HSV) can lead to productive infection or to latency, where the genomes persist in the nuclei of peripheral neurons in a quiescent state. Using the HSV strain d109, which does not express any viral genes and thus establishes a quiescent state in most cells, we observed that a fraction of genomes circularized upon infection. The expression of infected cell protein (ICP) 0, which is known to be involved in reactivation from latency and the promotion of productive infection, inhibited the formation of circular genomes. Circular genomes were not observed upon infection of fully permissive cells by wild-type virus, in either the presence or absence of viral DNA replication. However, productive infection in the absence of ICP0 resulted in the accumulation of a subpopulation of circular genomes. The proportion of circular genomes formed during infection with an ICP0 mutant was greater at low multiplicity of infection, a condition in which ICP0 mutants replicate poorly. In the complete absence of viral gene expression, it was found that only circular genomes persisted in cells. These results suggest that circularization of the HSV genome may not occur early in the productive phase of wild-type HSV infection, but rather during establishment of a quiescent state or latency, providing a possible strategy for long-term persistence. Additionally, the circularization and possible fate of HSV genomes are regulated by an activity of ICP0. Herpes simplex virus 1 (HSV-1) can establish both productive and latent infections. Productive infection with HSV-1 results in epithelial lesions, such as cold sores, and can lead to latent infection in the trigeminal ganglia of neurons that innervate the primary site of infection (1). During latency, the viral genome persists in a largely repressed, chromatin-associated state (2) that can be derepressed or reactivated to produce recurrent productive infections. The HSV-1 immediate early (IE) infected cell protein (ICP) 0 is crucial for reactivation (3-5).The HSV genome is a linear double-stranded DNA molecule existing as four isomers that differ with respect to the orientation of a long and a short region about a joint (6, 7). Both the long and short regions are bracketed by inverted repeats, and a 250-to 500-bp sequence (termed the ''a'' sequence) is directly repeated at the genomic termini (8-11). Inverted copies of the a sequence are also present at the joint. During both productive and latent infections, the genome assumes a configuration indicative of end-joining, because genomic joint sequences increase in abundance relative to their homologous counterparts at the genomic termini (12-15). End-joining can occur in the presence of inhibitors of protein synthesis, which has been interpreted as the circularization of the HSV genome as a function of cellular mechanisms (12, 13). Consequently, it is thought that circularization of viral genomes occurs before the onset of productive or latent infections, suggesting that this process occurs...

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mentioning

confidence: 67%

Relationship of herpes simplex virus genome configuration to productive and persistent infections

Jackson

DeLuca

2003

Proc. Natl. Acad. Sci. U.S.A.

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119

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“…[49][50][51][52][53] The establishment of a rd HSV strain devoid of all IE genes yielded a nontoxic vector. 54 Evidence has mounted that points to the viral IE ICP0 protein as a major cause of these toxicities, [55][56][57] most likely because of its ability to inhibit cell cycle progression. 58,59 The common feature of all of these vectors is that they are deleted for ICP4 and it has long been known that IE gene expression is elevated during infection in the absence of ICP4.…”

Section: Discussionmentioning

confidence: 99%

Viral oncoapoptosis of human tumor cells

Aubert

Blaho

2003

Gene Ther

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Many cancer cells refractory to radiation treatment and chemotherapy proliferate because of loss of intrinsic programmed cell death (apoptosis) regulation. Consequently, the resolution of these cancers are many times outside the management capabilities of conventional therapeutics. We now report that replication-defective D27 herpes simplex virus (rd D27) triggers apoptosis in three representative transformed human cell lines. Susceptibility to virus-induced cell death is dependent on the abundance and distribution of modified p53 protein in the tumor cells indicating specific targeting of the treatment. Primary human and mouse fibroblast cells that produce modified p53 are resistant to rd D27 killing but not to apoptosis induced by nonviral environmental factors. These results suggest that induction of apoptosis by nonreplicating virus is a feasible genetic therapy approach for killing human cancer cells. Our findings may have important implications in designing novel virus-based anticancer strategies in appropriate animal model systems.

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“…This process is dependent on the RING ®nger of ICP0 (Everett et al, 1998a) and probably requires only low levels of the protein (Hobbs et al, 2001). Transfection experiments have con®rmed that ICP0 leads to failure to accumulate SUMO-1 modi®ed forms of PML expressed from a co-transfected plasmid (Muller and Dejean, 1999), and furthermore that ICP0 by itself induces proteasome-dependent degradation of both modi®ed and unmodi®ed PML isoforms (Parkinson and Everett, 2000).…”

Section: Hsv-1 and Icp0mentioning

confidence: 99%

DNA viruses and viral proteins that interact with PML nuclear bodies

Everett¹

2001

Oncogene

230

238

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Connections between PML nuclear bodies (PML NBs) and DNA virus replication have been investigated from the earliest days of the molecular characterization of PML and associated proteins. It appears to be a general feature of nuclear-replicating DNA viruses that their parental genomes preferentially become associated with PML NBs, and that their initial sites of transcription and development of DNA replication centres are frequently juxtaposed to these domains or their remnants. In addition, regulatory proteins encoded by several DNA viruses associate with and sometimes cause catastrophic changes to PML NBs by a variety of mechanisms. These events can be correlated with the eciency of viral infection and the functions of viral regulatory proteins, but the underlying molecular connections between PML NB function and viral infection remain poorly understood. This article reviews the latest developments in the interactions between PML NBs and herpesviruses, adenoviruses and papovaviruses. Oncogene (2001) 20, 7266 ± 7273.

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Efficient Activation of Viral Genomes by Levels of Herpes Simplex Virus ICP0 Insufficient To Affect Cellular Gene Expression or Cell Survival

Cited by 47 publications

References 58 publications

Relationship of herpes simplex virus genome configuration to productive and persistent infections

Relationship of herpes simplex virus genome configuration to productive and persistent infections

Viral oncoapoptosis of human tumor cells

DNA viruses and viral proteins that interact with PML nuclear bodies

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