Tuesday, April 7, 2015

Purging a virus from organ transplants

Lausanne: Scientists have discovered the switch that can awake a dormant cytomegalovirus, a dreadful pathogen in immuno-compromised patients. The switch can be controlled with common drugs, opening a new strategy for purging the virus from organ transplants. Human cytomegalovirus (HCMV) is an extremely common herpes-family virus that infects people for life. It infects 60% of the population in industrialized countries, and almost everybody in poorer regions. Its symptoms are easily fought off by a healthy immune system, but can be devastating to individuals with defective immunity, e.g. newborn babies, people with AIDS, or those taking immunosuppressive drugs after receiving organ transplants. After infection, HCMV hides ("lies dormant") in blood-making stem cells, occasionally reactivating as these cells mature.

Scientists at EPFL have now discovered the molecular switch that allows HCMV to either lie dormant in these cells or reactivate and start infecting again. The switch can be manipulated with simple drugs to force HCMV reactivation, making the virus easy to target and kill. Published in eLife, the study shows how HCMV could be fought in high-risk patients and purged from organs before transplantation.
Throwing the switch
The lab of Didier Trono at EPFL discovered a protein that switches HCMV between dormancy and reactivation. They found this protein to be bound to the HCMV genome in latently infected hematopoietic stem cells and, upon a variety of external stimuli, to undergo a modification that allows for viral activation. The researchers were able to control this switch with a drug called chloroquine, usually used against malaria. When they treated blood-making stem cells that contained dormant HCMV with chloroquine, the virus reactivated and became exposed, opening the door to maneuvers aimed at eliminating virus-infected cells.
The simplicity of the study’s design underlies its enormous significance. On one hand, it sheds light on the molecular mechanism by which HCMV becomes dormant in hematopoietic stem cells, possibly offering insights into similar infections by other herpes viruses. On the other hand, the study provides a straightforward method for forcing HCMV out of dormancy in infected tissue. Coupled with a simultaneous dose of an antiviral, this could become a standard regimen for eradicating HCMV from high-risk patients and purging it from tissue before transplantation.
Trono’s team is now testing the method’s efficiency in purging HCMV from cells to be used for bone marrow transplantation. Following that step, the group will be developing the first trials in humans.
Rauwel B, Jang SM, Cassano M, Kapopoulou A, Barde I, Trono D. Release of Human Cytomegalovirus from latency by KAP1/TRIM28 phosphorylation switch. eLife DOI: 10.7554/eLife.06068