Oncogenic Herpes Virus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication; “Stress-Sensor” Proteins Slow Down Cell Proliferation Stimulating Virus Lytic Gene Expression

Researchers have now found an important link between cellular stress responses, cell cycle regulation, and the reactivation of an oncogenic herpes virus. While looking for cellular factors involved in the reactivation of a particular oncogenic human herpes virus, the Kaposi's-sarcoma-associated herpes virus (KSHV), the research group of Dr. Päivi Ojala at the University of Helsinki, Finland, and collaborators, have identified a mechanism by which stress conditions favor the lytic reactivation and ensure the efficient production of progeny viruses. KSHV is the etiological agent for Kaposi’s sarcoma and for primary effusion lymphoma (PEL), an aggressive form of lymphoma with reported median survival time shorter than six months after diagnosis. Results of the new study, which combined the most advanced microscopy technologies with genetic manipulation techniques, show that a variety of chemical stresses all lead to the activation of a set of cellular "stress-sensor" proteins – like p53 and p21clip – that, in the attempt to rescue the cell from the exogenous stress slow down cell proliferation. This process seems to create a cellular environment that favors the expression of viral lytic genes, which a few hours after reactivation leads to massive damage of the cellular DNA and arrest of the cell division cycle in a stage known as Gap-2 phase or G2. In this state, cells are kept alive by viral proteins and all cellular nutrients and resources are redirected to the assembly of thousands of new virions. The p21clip protein has a critical role in maintaining cells in the G2-arrested state, the research shows, as removal of this protein by genetic manipulation restored cell division in cells undergoing lytic replication.
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