Investigation of Marek's Disease Virus latency and reactivation via telomere integration in chickens

Marek's Disease Virus (MDV) is a major chicken pathogen that causes rapid-onset T-cell lymphomas and very high levels of mortality in poultry. In the late 1960s, a vaccine (the first ever produced against a cancer) was developed and used to protect birds. The vaccine is administered either in ovo to the developing embryo or into one-day old birds immediately after hatching. Vaccination does not prevent infection but it reduces the rate of progression from MDV latency to lymphoma. However, this vaccination-based control strategy is threatened by the evolution of increasingly virulent MDV. Currently the global annual economic losses from Marek's disease (MD) is estimated to be US$ 2 billion and this is likely to increase as vaccination becomes less effective.

Following initial infection MDV enters a latent state, through somatic integration into multiple telomeres in the target T cells. Clonal populations of T-cells harbouring latent copies of the viral genome undergo transformation giving rise to T-cell lymphomas and death of the bird within a few weeks. MDV shares its capacity to integrate into telomeres with two species of Human Herpes Virus-6 (HHV-6A and HHV-6B). Data support a model in which the HHV-6 genome can escape from the telomere via telomere-loop formation that includes the viral genome. Excision of the DNA loop releases an intact circular viral genome and could be the first step towards viral reactivation. It is hypothesised that a similar model underlies the transition between MDV latency following telomeric integration and reactivation leading to neoplasia in chickens.

The aim of this research project is to understand the relationship between telomere molecular biology in the chicken and MDV during integration, latency and reactivation. In addition, the project aims to investigate whether in telomere-related genes contribute to the genetic resistance seen in some chicken lines.