Marek's disease avian herpesvirus - Learning from differences

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Herpesviruses are large double-strand DNA viruses that cause disease in different animals. Marek's disease virus (MDV) is a highly oncogenic avian alphaherpesvirus. Marek's disease (MD) is characterized by CD4+ T-cell lymphomas in latently infected chicken cells. At $1-2B/year in worldwide costs, MD is one of the most significant chronic disease problem for the poultry industry. MDV shares many characteristics of herpesviruses, but its infection and vaccine action have several unique features. Taking advantage of these unique features, my long-term goal is to gain mechanistic insights into herpesvirus pathogenesis and vaccine prevention. My short-term goals are: 1) to investigate how MDV generates progeny virus from latency to better understand how herpesviruses replicate, and 2) elucidate how MD vaccines prevent lymphoma without eliminating virulent virus infection. All herpesviruses are able to establish latent infection in host cells. Upon stimulation, the latently infected herpesvirus is reactivated and resumes progeny virus production using a circularized genome as a template for the rolling-circle model of replication. This proposed model does not, however, explain how sufficient numbers of circularized templates are generated to support the explosive nature of virus reproduction. Aim 1: Unlike most other herpesviruses, the MDV genome integrates into host chromosomes during latency. I hypothesize alternate lengthening of telomere (ALT) is the mechanism by which the integrated MDV genome is excised prior to replication. Tumor cells use ALT to elongate telomere sequence to prevent senescence. During ALT telomere elongation, a circular partially double strand DNA is excised. I will use molecular biology methods such as RNAi and FISH to examine if ALT excises and circularizes the integrated MDV genome. If so, ALT may work in tandem with the rolling-circle model to create additional copies of circular virus genome templates for MDV as well as non-integrating herpesviruses. Aim 2: While other viral vaccines prevent disease by inducing adaptive immune responses to eliminate the virus, MD vaccines prevent lymphoma without eliminating virulent viral infection. MD vaccines prevent latently infected lymphocytes from expressing a viral protein, MEQ. MEQ is an MDV-encoded oncogene whose expression is essential for the oncogenesis. I hypothesize the MD vaccine eliminates the subset of T-cells that are capable of undergoing transformation by providing intranuclear environment for the expression of MDV MEQ. I will combine recombinant virus and proteomics techniques to test if MD vaccine eliminates these cells by immunologically stimulating prior to the virulent MDV challenge, rendering them incapable of expressing MEQ in latency. Elucidation of MDV pathogenesis and MD vaccine action mechanisms will provide essential evidence to make informed predictions regarding risk of future MD vaccine breaks and develop new anti-herpesvirus drugs.