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Title: Comparative sequence analysis of a highly oncogenic but horizontal spread-deficient clone of Marek's disease virus

item Spatz, Stephen

Submitted to: Herpesvirus International Workshop
Publication Type: Proceedings
Publication Acceptance Date: 5/31/2007
Publication Date: 7/7/2007
Citation: Spatz, S.J., Zhao, Y., Petherbridge, L., Smith, L.P., Baigent, S.J., Nair, V. 2007. Comparative sequence analysis of a highly oncogenic but horizontal spread-deficient clone of Marek's disease virus [abstract]. 32nd Annual International Herpesvirus International Workshop. Paper No. 6.24.

Interpretive Summary:

Technical Abstract: Marek’s disease virus (MDV) is a cell-associated alphaherpesvirus that induces T-cell lymphomas in poultry. MDV isolates vary greatly in pathogenicity. While some are non-pathogenic and are used as vaccines, others such as RB-1B are highly oncogenic. Comparison of the genome sequences of phenotypically different strains could help to identify molecular determinants of pathogenicity. We have previously reported the construction of bacterial artificial chromosome (BAC) clones of RB-1B. Viruses reconstituted from most of these clones were phenotypically similar to parental wild type virus. One clone (pRB-1B-22), however, generated a virus that was unable to spread horizontally to sentinel birds even though viral DNA could be detected in the feather follicles of infected bird. In vitro and in vivo replication kinetics studies indicated that this virus replicated to high titers and was equally oncogenic as the parental virus. The complete nucleotide sequence of this horizontal spread-negative virus was determined and by comparison to the sequences of transmission-competent strain (Md5), 42 non-synonymous mutations were identified in 22 ORFs. Moreover, frameshift mutations were identified in several ORFs: RLORF1, protein kinase (UL13) and glycoproteins C (UL44) and D (US6). Due to the nature of the frameshift mutations, only the US6 gene is likely to encode a functional protein. If alternative ATG codons are used, two proteins (UL13A and UL13B) and (UL44A and UL44B) are predicted from the UL13 and UL44 genes, respectively. In each case these proteins would lack function since domains important for kinase activity are divided among the two UL13 proteins and a signal sequence would be missing if the downstream ATG codon in the UL44 gene was used. The use of the first start codon would result in the production of a 30 aa protein (UL44A). Sequence analysis of these genes from the genome of the parental RB1B virus indicated that the RLORF1, UL44 and US6 mutations were present in the transmission-competent parental stock. Interestingly, both the wild type and mutant sequences within UL44 could be demonstrated in these stocks. This indicated that only the UL13 mutation was introduced during the construction of pRB-1B-22. The possible involvement of the UL13 protein kinase and glycoprotein C in egress is intriguing in light of research indicating essential roles for these two proteins in skin infectivity of the related cell-associated varicella-zoster virus.