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The herpes simplex virus type 1 UL3 transcript starts within the UL3 open reading frame and encodes a 224-amino-acid protein.

ABSTRACT: Several different herpes simplex viruses (HSVs) and vectors are being explored as therapeutic products for use in the treatment of cancer and neurological disorders. The viral strain and the combination of mutant viral genes that ultimately may serve as a safe and optimal backbone for such products are still being explored. The large genome size and complexity of the viral life cycle make such determinations difficult, because the significance of differences between proposed products is difficult to evaluate. For example, we previously reported that two lineages of gamma34.5-deleted HSVs used in clinical studies differ from each other in the size of the UL3 protein expressed (M. J. Dambach et al., Mol. Ther. 13:891-898, 2006). Because the function of UL3 is not known and UL3 gene expression is poorly understood, the significance of such a difference cannot be predicted. Here, I begin to address the function of UL3 by investigating UL3 gene expression. I report that the transcript start site of UL3 mRNA isolated from HSV type 1 (HSV-1)-infected cells maps to a position downstream of the predicted translation start site. By constructing and characterizing the recombinant virus CB8116, which has a mutation in the first in-frame start codon of this UL3 transcript, I demonstrated that UL3 protein translation initiates at the second in-frame start codon of the UL3 open reading frame. This information adds to the body of basic knowledge of HSV-1 biology that forms the foundation for our current understanding of HSV-based products. Future research on HSV-1 biology will facilitate the rational design and evaluation of future generations of therapeutic viruses.

SUBMITTER: Markovitz NS

PROVIDER: S-EPMC2045449 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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The herpes simplex virus type 1 UL3 transcript starts within the UL3 open reading frame and encodes a 224-amino-acid protein.

Markovitz Nancy S NS

Journal of virology 20070711 19

Several different herpes simplex viruses (HSVs) and vectors are being explored as therapeutic products for use in the treatment of cancer and neurological disorders. The viral strain and the combination of mutant viral genes that ultimately may serve as a safe and optimal backbone for such products are still being explored. The large genome size and complexity of the viral life cycle make such determinations difficult, because the significance of differences between proposed products is difficul ...[more]

PMID: 17626086

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Project description:UnlabelledThe herpes simplex virus 1 (HSV-1) ICP34.5 protein strongly influences neurovirulence and regulates several cellular antiviral responses. Despite the clinical importance of HSV-2, relatively little is known about its ICP34.5 ortholog. We found that HSV-2 produces up to four distinct forms of ICP34.5 in infected cells: a full-length protein, one shorter form sharing the N terminus, and two shorter forms sharing the C terminus. These forms appeared with similar kinetics and accumulated in cells over much of the replication cycle. We confirmed that the N-terminal form is translated from the primary unspliced transcript to a stop codon within the intron unique to HSV-2 γ34.5. We found that the N-terminal form was produced in a variety of cell types and by 9 of 10 clinical isolates. ICP27 influenced but was not required for expression of the N-terminal form. Western blotting and reverse transcription-PCR indicated the C-terminal forms did not contain the N terminus and were not products of alternative splicing or internal transcript initiation. Expression plasmids encoding methionine at amino acids 56 and 70 generated products that comigrated in SDS-PAGE with the C1 and C2 forms, respectively, and mutation of these sites abolished C1 and C2. Using a recombinant HSV-2 encoding hemagglutinin (HA)-tagged ICP34.5, we demonstrated that the C-terminal forms were also produced during infection of many human and mouse cell types but were not detectable in mouse primary neurons. The protein diversity generated from the HSV-2 γ34.5 open reading frame implies additional layers of cellular regulation through potential independent activities associated with the various forms of ICP34.5.ImportanceThe herpes simplex virus 1 (HSV-1) protein ICP34.5, encoded by the γ34.5 gene, interferes with several host defense mechanisms by binding cellular proteins that would otherwise stimulate the cell's autophagic, translational-arrest, and type I interferon responses to virus infection. ICP34.5 also plays a crucial role in determining the severity of nervous system infections with HSV-1 and HSV-2. The HSV-2 γ34.5 gene contains an intron not present in HSV-1 γ34.5. A shorter N-terminal form of HSV-2 ICP34.5 can be translated from the unspliced γ34.5 mRNA. Here, we show that two additional forms consisting of the C-terminal portion of ICP34.5 are generated in infected cells. Production of these N- and C-terminal forms is highly conserved among HSV-2 strains, including many clinical isolates, and they are broadly expressed in several cell types, but not mouse primary neurons. Multiple ICP34.5 polypeptides add additional complexity to potential functional interactions influencing HSV-2 neurovirulence.

Dataset Information

The herpes simplex virus type 1 UL3 transcript starts within the UL3 open reading frame and encodes a 224-amino-acid protein.

Publications

The herpes simplex virus type 1 UL3 transcript starts within the UL3 open reading frame and encodes a 224-amino-acid protein.

Similar Datasets

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