Working Towards a Way to Clear Cytomegalovirus

Like other herpesviruses, cytomegalovirus (CMV) cannot be effectively naturally cleared from the body as it has evolved the means to hide from the immune system. It is harmless for most people in the short term, but over the long term it causes ever more of the limited supply of immune cells to become uselessly devoted to fighting it. Since near everyone is exposed to CMV by the time they are old, this appears to be an important contribution to the age-related decline of the immune system.

One possible approach to dealing with this issue is to selectively destroy CMV-specialized immune cells. They will be replaced naturally and fairly quickly, or that replacement can be hurried along with an infusion of immune cells grown from a sample of the patient's tissues. The cancer research community is a fair way along in the development of highly selective cell destruction technologies that identify targets based on their distinctive surface chemistry, and this work can be adapted for use in winnowing the immune system.

Another approach is to find ways to clear out CMV, but that isn't so helpful for people who have lived with it for a long time and are therefore already suffering the consequences in the form of a distorted balance of immune cells. Nonetheless, here is a look at research into how CMV hides from the immune system. This is a starting point on the path towards disabling these molecular mechanisms to enable immune cells to clear CMV from the body:

Human cytomegalovirus (HCMV) is a herpesvirus that infects most people in the world, usually without producing symptoms. However, infection is life-long and must be kept in check by the immune system. When the immune system is weakened, the outcome of HCMV infection can be very serious. Thus, HCMV is the major cause of birth defects resulting from infection of the fetus during pregnancy, and it can cause severe disease in people with a weakened immune system, especially transplant recipients and HIV/AIDS patients. One type of immune cell, the natural killer (NK) cell, is crucial in controlling cells in the body that are abnormal. They do this by recognizing cells, which have special stress proteins on their surface, and killing them. When cells are infected with HCMV, they start to make these stress proteins. However, the virus has evolved ways to stop NK cells from killing infected cells by quickly stopping the stress proteins from reaching the surface. We have now identified two HCMV genes that target a major stress protein (called MICA) and cause its rapid destruction. Removing these two genes from HCMV renders infected cells very susceptible to killing by NK cells. This discovery might help the development of new ways to fight HCMV.

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells. Despite [activation], HCMV effectively suppressed cell surface expression of NKG2D ligands through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2D ligands. While infection with a UL16 deletion mutant caused the expected increase [in NKG2D ligand] cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert.



Would long-term acyclovir (such as in HSV) have any potential to suppress the virus enough to prevent immune cell wasting? It seems logical enough.

Posted by: Chris W. at August 15th, 2014 4:12 AM

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