Sequence determination and genetic content of the short unique region in the genome of herpes simplex virus type 1

doi:10.1016/0022-2836(85)90320-1

Journal of Molecular Biology

Volume 181, Issue 1, 5 January 1985, Pages 1-13

https://doi.org/10.1016/0022-2836(85)90320-1 Get rights and content

Abstract

We have determined the complete DNA sequence of the short unique region in the genome of herpes simplex virus type 1, strain 17, and have interpreted it in terms of messenger RNAs and encoded proteins. The sequence contains variable regions whose length differs between DNA clones. The clones used for most of the analysis gave a short unique length of 12,979 base-pairs. We consider that this region contains 12 genes, which are expressed by mRNAs which have separate promoters, but may share 3′-termination sites, so that all but two mRNAs belong to one of four 3′-coterminal “families”: 79% of the sequence is considered to be polypeptide coding. One pair of genes has an extensive out-of-frame overlap of coding sequences. The proteins encoded in the short unique region include two immediate-early species, two virion surface glycoproteins, and a DNA-binding species. Six of the genes have little or no previous characterization. From the nature of the amino acid sequences predicted for their encoded proteins, we deduce that several of these proteins may be membrane-associated.

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Citation Excerpt :
Viral DNA was obtained from 200 μl of viral stock by means of QIAamp® DNA blood mini kit (Qiagen, Hilden, Germany). The oligonucleotide primers for the amplification and sequencing of TK (UL23) and DNA pol (UL30) genes based on the HSV-1 reference strain 17 (GenBank Accession No. X14112) (McGeoch et al., 1985) were used as described previously (Sauerbrei et al., 2011). The TK gene of all HSV-1 cell culture isolates could be amplified as one fragment whereas the DNA pol gene was amplified in four separate fragments.
The role of mutations in the thymidine kinase (TK, UL23) and DNA polymerase (pol, UL30) genes of herpes simplex virus (HSV) for development of different resistance phenotypes has to be exactly determined before genotypic resistance testing can be implemented in patient’s care. Furthermore, the occurrence of cross-resistance is of utmost clinical importance. In this study, clinical HSV-1 isolates obtained between 2004 and 2011 from 26 patients after stem cell transplantation were examined in parallel by phenotypic and genotypic resistance testing. Thirteen isolates, which were phenotypically cross-resistant to acyclovir (ACV), penciclovir (PCV) and brivudin (BVDU), exhibited consistently frameshift or non-synonymous mutations in the TK gene known to confer resistance. One of these mutations (insertion of C at the nucleotide positions 1061–1065) has not been described before. Seven strains, phenotypically resistant to ACV and PCV and, except one each, sensitive to BVDU and resistant to foscarnet (FOS), carried uniformly resistance-related substitutions in the DNA pol gene. Finally, 3 isolates, resistant to ACV, PCV and 2 out of these also resistant to BVDU, had known but also unclear substitutions in the TK and DNA pol genes, and 3 isolates were completely sensitive. In conclusion, clinical ACV-resistant HSV-1 isolates, carrying resistance-associated mutations in the TK gene, can be regarded as cross-resistant to other nucleoside analogs such as BVDU. In contrast, clinical FOS-resistant HSV-1 strains which are cross-resistant to ACV may be sensitive to BVDU. This has to be considered for drug changes in antiviral treatment in case of ACV resistance.

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Journal of Molecular Biology

Sequence determination and genetic content of the short unique region in the genome of herpes simplex virus type 1

Abstract

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