Background Long-term persistence in the infected host is a key feature of the known oncogenic infectious agents and is an appealing target for therapy. Work described in this sub-project aims to increase our understanding of the molecular mechanisms involved in persistence and how they could be exploited for therapeutic intervention, which is a central aim of INCA. There are thematic links to other SPs, such as genetic polymorphism (SP2) as well as the interaction of pathogen components with intracellular responses (SP3-4) may contribute to persistence. Translational aspects from SP1 are also found in SP5; in addition, work on BLV in SP5 is having a translational impact on HTLV-1 work in SP1. Specific objectives To investigate the latent persistence of episomally replicating DNA viruses, with the aim of identifying targets for pharmacological intervention. To investigate the role of chromatin modification in the latency and reactivation of oncogenic herpesviruses and retroviruses, with the aim of exploring the therapeutic potential of chromatin-modifying agents for the therapy of virus-associated cancer. To investigate how oncogenic viruses and bacteria persist by adapting to particular cells or tissues and by interfering with – or avoiding – the innate and adaptive immune systems.

Scientific approach Three complementary programmes of experiments are underway, each addressing a different type of mechanism that is thought to contribute to the persistence of the pathogen in vivo. 1. Episomal replication of latent HPV and KSHV genomes In this section we will test the hypothesis that specific proteins encoded by papillomaviruses (HPV) and herpesviruses (KSHV) control the transcription and replication of these viruses. 2. Chromatin modification and latent persistence Chromatin acetylation and DNA methylation may play a role in maintaining viral latent persistence of the human oncogenic retrovirus HTLV-I, papillomaviruses and KSHV. The aim of SP1 is to test whether chromatin-modifying agents could be used to interfere with latent persistence by tilting the host-pathogen balance towards an existing antiviral T cell response or mechanisms of intracellular antiviral surveillance. 3. Persistence of oncogenic pathogens by adaptation and escaping the immune response H. pylori manages to persist by escaping host defense mechanisms. We are studying the expression, distribution and redistribution of different TOLL-like receptors and chemokine receptors upon contact of H. pylori with human gastric and intestinal epithelial cells. We also study the mechanisms underlying the exceptionally high genetic variability of H. pylori and the role of this variation in chronic infections. Results and relevance: contribution to the whole project SP1 will deliver the following results: Identify E8^E2C – binding cellular proteins with a role in latent HPV replication Establish that the interaction of LANA with brd proteins can be a target for attempts to block latent KSHV replication; obtain small peptide – based or chemical inhibitors of this interaction and evaluate their influence on latent replication, Establish the role of histone modifications in HTLV-I, HPV and KSHV persistence and reactivation. Evaluate the potential of HDAC and methyltransferase inhibitors to reactivate HTLV-I from ATL cells and the potential of Tax – specific CTLs to eliminate cells in which HTLV-I reactivation has occurred Establish the nature of cell death signals and pathways in ATL cells following viral reactivation Investigate how H. pylori escapes components of the innate immune system Investigate mechanisms H. pylori uses to adapt to the host by genetic variation. Identify the cell type responsible for the long-term persistence in vivo of KSHV and viral genes required for longterm in vivo persistence The results of this work will promote our knowledge of fundamental issues surrounding the latent persistence of oncogenic viruses and bacteria, as well as work towards the generation of inhibitors of latent replication or persistence.