Marek's disease virus latency and reactivation: the role of telomeres in integration and mobilization of viral DNA

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• Professor Klaus Osterrieder, Free University, Berlin
• Thursday 14 October 2010, 12:00-13:00
• Sackler Lecture Theatre, Level 7, CIMR, Addenbrooke’s Hospital.

If you have a question about this talk, please contact Sue Griffin.

Hosts: Truus Abbink, gema2@cam.ac.uk & Jim Kaufman, jfk31@cam.ac.uk

Research Interests: Our group is interested in the replication and pathogenesis of animal herpesviruses such as equine herpesvirus type 1 (EHV-1), Marek’s disease virus (MDV) and varicella zoster virus (VZV).

Equine herpes virus 1 (EHV-1) Immunomodulatory proteins: Our aim is to evaluate the role of EHV -1 glycoproteins in the pathogenesis of this virus. Some of these glycoproteins have been shown to have immunomodulatory properties, such as glycoprotein G (gG) which binds chemokines with high affinity. Furthermore, the UL49 .5 product, which has TAP inhibitory activity, i.e. it prevents transport of proteasome-generated peptides into the ER and thereby their presentation by MHC class molecules.

We cloned EHV -1 isolates as bacterial artificial chromosomes (BAC), which we will use to make mutants that are either unable to express gG or unable to produce its secreted form. The mutant viruses will be tested in vivo for their growth properties and virulence in the natural host. We will also test the growth properties of a UL49 .5-negative mutant in horses and examine the molecular mechanism underlying TAP inhibition by the UL49 .5 product.

Development of EHV -1 as an immunization and/or gene therapy vector: We investigate the possibilities of using EHV -1 as a vector to deliver foreign genes to equines and other mammals, including humans. We have generated mutants expressing antigens from West Nile virus, equine and avian influenza virus, Venezuelan equine encephalitis virus, or the human pathogen hepatitis C virus. These constructs have already been tested in mice and we plan to administer them to either the target species (animals) or primates for the induction of insert-specific and sustained immune responses.

Marek’s Disease Virus (MDV) MHC class I down-regulation and production of mutant MDV random mutagenesis: We have identified proteins that may play an important role in MHC class I downregulation, but we expect several proteins to be involved in this targeted interference with the host’s immune response to infection. We plan at identifying the mechanism underlying this immune evasion mechanism by several different approaches, including MHC class I maturation studies and studies of protein-protein interactions.

Role of glycoprotein C (gC) in tumor formation: We were able to show that MDV gC is expressed as three different moieties, one cell associated, two secreted, which are generated by a splicing event. The hypothesis to be tested is that gC expression is involved in MDV tumor formation and horizontal virus spread.

Role of telomerase RNA and telomeric repeat sequences in MDV pathogenesis: MDV induces a highly malignant T cell lymphoma in its primary host, the chicken. Telomerase performs an important function in the cellular survival program by maintaining the integrity of chromosomes through amplification of telomeric repeats. MDV harbors in its genome two copies of a viral telomerase RNA (vTR), which appears to play a direct role in lymphomagenesis and tumor metastasis. Our long-term goal is to elucidate in detail the mechanisms of the tumor-promoting effects of telomerase. This natural small animal model of virus-induced lymphoma allows us to interfere with telomerase activity by specifically altering the structure and/or levels of (v)TR in infected cells.

Varicella zoster virus Generation of a BACs and preliminary testing of selected mutant viruses: The understanding of VZV pathogenesis and the development of novel well-characterized vaccines have been complicated by the difficulties in mutant virus generation. We introduced BAC technology to VZV research and first analysed the structural function of the VZV ORF9 product, a putative tegument protein. This protein was shown to be essential for virus growth. In future studies, we will analyze open reading frames that are involved in immune evasion and localized at genomic termini.

This talk is part of the Immunology in Pathology series.

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