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Host factors determining latency and reactivation of MDV-1 virus

  • Full or part time
  • Application Deadline
    Friday, March 29, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Herpesviruses are large dsDNA viruses that cause widespread, lifelong latent infections in different hosts, through multiple virus-host interactions to create a delicate balance between the virus and the host. CRISPR/Cas9-based gene editing is emerging as a powerful tool to investigate the precise determinants of latency in a number of herpesvirus infections. Marek’s disease virus (MDV-1) is a lymphotropic α-herpesvirus associated with latent infections and malignant CD4+ T-cell lymphomas in chicken. The rapid onset of tumours in Marek’s disease (MD) makes it an ideal virus-induced lymphoma model in its natural host. MDV-1 has a two-phase life cycle, consisting of a lytic and a latent phase, the latter closely associated with the oncogenesis of the virus, yet the underlying molecular mechanisms of cell transformation remain unclear. Several viral genes such as Meq, vTR, vIL-8 and MDV1-miR-M4-5p, have been directly implicated in the oncogenic process.
Two major questions in this field are to understand (1) the factors that maintain the latency of the virus and (2) how the virus is reactivated from the latent state. Our hypothesis is that MDV latency and transformed phenotype in lymphoblastoid cell lines such as MSB-1 and HP8 is maintained by altered expression of a number of critical host genes, and that knockout of these gene(s) using a genome-wide screen approach can induce latency to lytic switch. Better understanding of these processes will provide insights into novel intervention strategies to interfere with the neoplastic process. We will use a high throughput genome-wide CRISPR/Cas9 gene knockout strategy, combined with next generation sequencing to identify the genes critical for both latent to lytic switch and maintenance of the transformed phenotype.

Funding Notes

This is a fully funded studentship open to science graduates (with or who anticipate obtaining at least 2.1 or equivalent in relevant biological subject in undergraduate degree, or a Masters degree - subject to university regulations). Open to UK students and eligible EU students who qualify for home-rated fees in line with UKRI Residential Guidelines - Visit Website for details. Eligible students will receive a minimum annual stipend of £15,009; university registration fees will be paid. Students without English as first language must provide evidence of IELTS score of 7.0, no less than 6.5 in subsections.

References

1. Nair V, Kung HJ. 2004. Marek's disease virus oncogenicity: Molecular Mechanisms, p 32-48. In Davison F, Nair V (ed), Marek's Disease: An Evolving Problem, 1st ed. Elsevier Academic Press, London.
2. Nair V. 2013. Latency and tumorigenesis in Marek's disease. Avian Dis. 57(2 Suppl):360-5.
3. Zhang Y, Tang N, Sadigh Y, Baigent S, Shen Z, Nair V, Yao Y. 2018. Application of CRISPR/Cas9 Gene Editing System on MDV-1 Genome for the Study of Gene Function. Viruses 10.

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