Oncogenic Marek’s disease viruses lacking the 132 base pair repeats can still be attenuated by serial in vitro cell culture passages

Silva, R. F.; Gimeno, Isabel M.

doi:10.1007/s11262-006-0022-7

Cited by 18 publications

(7 citation statements)

References 13 publications

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“…At most they indicate the degree of passage or ''passage history'' that a strain has undergone in cell culture. It seems likely that other genetic changes besides the 132 bp expansion are responsible for attenuation [42].…”

Section: Genome Organization and Phylogenetic Relatednessmentioning

confidence: 99%

Sequence determination of a mildly virulent strain (CU-2) of Gallid herpesvirus type 2 using 454 pyrosequencing

Spatz

Rue

2008

Virus Genes

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The complete DNA sequence of the mildly virulent Gallid herpesvirus type 2 strain CU-2 was determined and consists of 176,922 bp with an overall gene organization typical of class E herpesviruses. Phylogenetically, this strain partitions in its own branch between the virulent strains RB-1B, Md11, and Md5, and the vaccine strain CVI988. Overall, the genome of CU-2 is more similar to that of CVI988, with identically sized unique short regions of 11,651 bp. As in CVI988, an insertion of 177 bp was identified in the overlapping genes encoding the Meq, RLORF6, and 23 kDa proteins within the repeat long region of the genome. A total of 15 single nucleotide polymorphisms (SNPs) common to both CU-2 and CVI988, and not occurring in virulent strains, were identified in the genes encoding UL29, UL45, UL50, UL52, LORF10, RLORF14a, RLORF12, Meq(RLORF7), 23kDa, ICP4, US3, and two hypothetical proteins MDV071.4 and MDV076.4. Each gene encoding UL29 and Meq contained two SNPs. Only one major open reading frame (ORF) encoding UL41, the virus host shutoff (VHS) ribonuclease, was disrupted in the CU-2 genome. An additional cytosine after the 25 codon is predicted to produce a truncated protein of 97 aa. Since GaHV-2 mutants lacking UL41 have been reported to retain their virulence, other factors are likely responsible for the low virulence of CU-2. It is largely suspected that SNPs in common with CVI988 along with the insertions in the Meq loci are responsible for its phenotype. Conversely, we identified 43 nonsynonymous mutations (within 23 genes) that may contribute to the virulence of CU-2. These SNPs are shared exclusively with all sequenced virulent strains (Md5, Md11, and RB-1B) and not present within the CVI988 genome. Although most occur in proteins of unknown function, a significant percentage is in proteins involved in virion assembly.

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Section: Genome Organization and Phylogenetic Relatednessmentioning

confidence: 99%

Sequence determination of a mildly virulent strain (CU-2) of Gallid herpesvirus type 2 using 454 pyrosequencing

Spatz

Rue

2008

Virus Genes

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“…Inoculation of MD-susceptible birds with a pp38 deletion mutant virus revealed that pp38 is involved in early cytolytic infection of lymphocytes, but not the induction of tumors [11]. Recently studies showed that the mechanism of attenuation of MDV does not involve the 132 bp repeat region [12]. Among these genes, only Meq is the most consistently expressed in latent phase [6] which is present in serotype 1 strains, but not in the non-oncogenic serotype 2 and serotype 3 strains [13,14].…”

Section: Introductionmentioning

confidence: 99%

Deletion of the meq gene significantly decreases immunosuppression in chickens caused by pathogenic marek's disease virus

Sun

et al. 2011

Virol J

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BackgroundMarek's disease virus (MDV) causes an acute lymphoproliferative disease in chickens, resulting in immunosuppression, which is considered to be an integral aspect of the pathogenesis of Marek's disease (MD). A recent study showed that deletion of the Meq gene resulted in loss of transformation of T-cells in chickens and a Meq-null virus, rMd5ΔMeq, could provide protection superior to CVI988/Rispens.ResultsIn the present study, to investigate whether the Meq-null virus could be a safe vaccine candidate, we constructed a Meq deletion strain, GX0101ΔMeq, by deleting both copies of the Meq gene from a pathogenic MDV, GX0101 strain, which was isolated in China. Pathogenesis experiments showed that the GX0101ΔMeq virus was fully attenuated in specific pathogen-free chickens because none of the infected chickens developed Marek's disease-associated lymphomas. The study also evaluated the effects of GX0101ΔMeq on the immune system in chickens after infection with GX0101ΔMeq virus. Immune system variables, including relative lymphoid organ weight, blood lymphocytes and antibody production following vaccination against AIV and NDV were used to assess the immune status of chickens. Experimental infection with GX0101ΔMeq showed that deletion of the Meq gene significantly decreased immunosuppression in chickens caused by pathogenic MDV.ConclusionThese findings suggested that the Meq gene played an important role not only in tumor formation but also in inducing immunosuppressive effects in MDV-infected chickens.

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“…First, there was no expansion of the 132 bp repeat sequences in the internal repeat long (IRL) region of the RM1 MDV genome. Although expansion of the 132 bp repeats typically occurs following repeated cell-culture passages, the expansion is not directly responsible for the ensuing attenuation [17,18]. Second, the RM1 strain was noticeably attenuated but still induced severe thymic and bursal atrophy, resulting in subsequent immunodepression.…”

Section: Introductionmentioning

confidence: 99%

Artificially inserting a reticuloendotheliosis virus long terminal repeat into a bacterial artificial chromosome clone of Marek’s disease virus (MDV) alters expression of nearby MDV genes

et al. 2011

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Researchers reported that co-cultivating the JM/102W strain of Marek's disease virus (MDV) with reticuloendotheliosis virus (REV) resulted in an REV long terminal repeat (LTR) being inserted into the internal repeat short (IRS) region of JM/102W. When the resulting recombinant virus was serially passed in cell culture, the initial LTR was duplicated and a second LTR spontaneously appeared in the terminal repeat short (TRS) region of the MDV genome. The virus, designated RM1, was significantly attenuated but still induced severe bursal and thymic atrophy (Isfort et al. PNAS 89:991-995). To determine whether the altered phenotype was due solely to the LTR, we cloned the LTR from the RM1 IRS region and inserted it into the IRS region of a very virulent bacterial artificial clone (BAC) of the Md5 strain of MDV, which we designated rMd5-RM1-LTR. During blind passage in duck embryo fibroblast cultures, the initial LTR in the rMd5-RM1-LTR was also duplicated, with LTRs appearing in both IRS and TRS regions of the MDV genome. The inserted LTR sequences and transcripts associated with the MDV open reading frames MDV085, MDV086, SORF2, US1, and US10 were molecularly characterized. The parental Md5 BAC contains a family of transcripts of 3, 2, and 1 kb that all terminate at the end of the US10 gene. The rMd5-RM1-LTR and RM1 viruses both express an additional 4 kb transcript that originates in the LTR and also terminates after US10. Collectively, the data suggest that our engineered rMd5-RM1-LTR virus very closely resembles the RM1 virus in its structure and transcription patterns.

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Oncogenic Marek’s disease viruses lacking the 132 base pair repeats can still be attenuated by serial in vitro cell culture passages

Cited by 18 publications

References 13 publications

Sequence determination of a mildly virulent strain (CU-2) of Gallid herpesvirus type 2 using 454 pyrosequencing

Sequence determination of a mildly virulent strain (CU-2) of Gallid herpesvirus type 2 using 454 pyrosequencing

Deletion of the meq gene significantly decreases immunosuppression in chickens caused by pathogenic marek's disease virus

Artificially inserting a reticuloendotheliosis virus long terminal repeat into a bacterial artificial chromosome clone of Marek’s disease virus (MDV) alters expression of nearby MDV genes

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