A Potential Approach to Clearing Cytomegalovirus

Cytomegalovirus (CMV) is a herpesvirus that causes few if any noticeable issues in most people when they are first exposed to it. By the time old age rolls around, near everyone tests positive for CMV. It is thought that the presence of this virus goes some way towards explaining the age-related decline of the adaptive immune system. The immune system has in effect a limited number of cells at any given time since the replacement rate is low in adults. Since CMV cannot be cleared from the body, and continually reemerges to challenge the immune system, ever more immune cells become devoted to battling CMV rather than defending the body from new threats.

It is worth keeping an eye on progress towards therapies capable of clearing CMV, but in old people even an excellent clearance treatment will likely be of little use. The damage has already been done at that point, the immune system already misconfigured and out of balance. What is needed is a way to selectively destroy the CMV-specialized cells to free up space and trigger their replacement with fresh immune cells.

Human cytomegalovirus (HCMV) is an extremely common virus, which as other members of the herpes virus family causes life-long infections in humans. Most individuals are exposed to HCMV during childhood, yet symptoms can be easily fought off by a healthy immune system. HCMV infects 60% of the population in industrialized countries, and almost everybody in less affluent places. This virus persists for life by hiding in blood-making ("hematopoietic") stem cells, where it lies dormant and goes completely unrecognized. It occasionally reactivates in the descendants of these hematopoietic stem cells, but these bouts are rapidly tamed by the immune system. However, in people whose immune system has been compromised, e.g. by AIDS, and organ transplant recipients who have to take immunosuppressive drugs, HCMV reactivation can cause devastating symptoms.

Researchers have 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. Furthermore, the researchers were able to control this switch with a drug called chloroquine, usually used against malaria. When they treated hematopoietic stem cells containing 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. Researchers are 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.

Link: http://www.eurekalert.org/pub_releases/2015-04/epfd-pav040215.php


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