Marelli, S;
(2017)
Characterization of molecular pathways regulating the latent-to-lytic switch in γ-herpesviruses.
Doctoral thesis , UCL (University College London).
Abstract
Human γ-herpesviruses 4 and 8 (also known as EBV and KSHV) are oncogenic viruses known primarily for their associations with Hodgkin Lymphoma and Kaposi Sarcoma respectively. Upon infection of target cells, γ-herpesviruses establish either a latent or a lytic viral cycle. Latency is characterized by expression of just a few viral oncogenes and microRNAs, whereas lytic replication leads to expression of virtually all of the virus encoded genes and release of infectious particles, leading to apoptosis of the host cell. The molecular mechanisms regulating the latent-to-lytic switch are poorly characterized, and a deeper understanding of it could lead to identification of specific targets for therapeutic intervention. Here I describe two novel molecular mechanisms leading to viral lytic replication. Firstly, I describe the requirement for viral microRNA miR-K10 for maintenance of steady state latency. I found that miR-K10 targets the transcription factor β-catenin, which can be triggered by stimulation of the Wnt pathway. Induction of β-cateninmediated transcription results in viral replication and virally-induced apoptosis in both EBV and KSHV. Because β-catenin activity is also induced by growth factors, we speculate that γ-herpesviruses have evolved to spread to neighbouring cells when the extracellular environment is rich in growth stimuli. I secondly describe the interplay of γ-herpesviruses with senescence, showing that senescent cells can be infected by KSHV, which there establishes a lytic but not a latent program. One of the major characteristics of cellular senescence is loss of telomerase activity. I show that inhibition of telomerase activity in non-senescent cells leads to viral replication of both KSHV and EBV. Thus, γ-herpesviruses do not establish latency in senescent cells, which would not perpetrate the viral genome. Given that both of these mechanisms can be pharmacologically targeted, this work suggests new avenues for the design of novel therapeutic strategies to treat γ-herpesvirus-associated malignancies.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | Characterization of molecular pathways regulating the latent-to-lytic switch in γ-herpesviruses |
| Event: | UCL (University College London) |
| Language: | English |
| UCL classification: | UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1559782 |
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