Viruses are masters of deception, duping their host's cells into helping them grow and spread. A new study has found that human cytomegalovirus (HCMV) can mimic a common regulatory protein to hijack normal cell growth machinery, disrupting a cell's primary anti-cancer mechanism. Writing in the May 9 issue of Science, researchers from the University of Wisconsin-Madison and Harvard Medical School report that a viral protein, called UL97, masquerades as a normal regulatory enzyme to modify a tumor-suppressing protein in human cells. Unlike the normal enzyme, which can be switched on and off by the cell as needed, the viral stand-in lacks an off switch and evades cellular control. The findings represent a previously unknown way that viruses can cause uncontrolled cell growth and division. Cells normally have tight regulatory mechanisms in place to limit multiplication to appropriate situations, such as replacing worn-out cells or repairing damage. Uncontrolled cell proliferation can lead to cancer and other disorders.

Leukotrienes (LTs) are powerful proinflammatory lipid mediators that may play a central role in cardiovascular diseases, including arteriosclerosis, myocardial infarction, and stroke. Owing to restricted expression of 5-lipoxygenase (5-LO), the enzyme required for their synthesis, LTs are almost exclusively produced by myeloid cells. Here, we report that human cytomegalovirus (HCMV) infection of human vascular smooth muscle cells (SMCs) increases 5-LO mRNA levels by up to 170-fold in a dose- and time-dependent manner. Infected cells expressed 5-LO protein, as shown by immunohistochemistry, enabling them to synthesize bioactive LTB4. HCMV-infected vascular SMCs expressing 5-LO protein were readily detected in tissue samples from CMV-infected patients with inflammatory bowel disease or AIDS. Thus, pathogen-induced LT production in HCMV-infected tissues may contribute to local inflammation, consistent with the ability of HCMV to control cellular and immunological functions. HCMV-induced LT biosynthesis in SMCs offers a molecular mechanism to explain HCMV-induced pathogenesis in inflammatory diseases.

A dormant virus that is awoken by inflammation enhances this potentially dangerous immune response to remain active. The human cytomegalovirus (HCMV) switches off its own replication after infection to stay off the immune system’s radar. Unlike other dormant viruses that require a weakened immune system to reactivate, HCMV thrives amidst a roaring immune response. The virus replicates when its host cells—monocytes and other inflammation-causing cell types—proliferate. These cells produce cytokines such as TNF that directly stimulate the promoters of some HCMV genes. Active HCMV infections are thus commonly found within the inflamed tissues of patients suffering from chronic inflammatory diseases, such as atherosclerosis. But whether the reactivated virus is just a lucky beneficiary of local inflammation or actively perpetuates inflammation was under debate. Researchers now find that HCMV enhances inflammation by coercing nearby noninflammatory cells to join the fray. Smooth muscle cells isolated from inflamed tissues harbored active HCMV and produced leukotrienes—powerful proinflammatory lipids. Leukotriene production had been thought to be restricted to immune cells. How the virus reprograms the previously harmless muscle cells to become inflammatory is not clear.

What's interesting (to me) about this paper is the link with cancer: they found that HCMV increases phosphofructokinase activity and decreases pyruvate kinase activity, similar to what happens in tumours. I also wonder whether some of the miRNAs expressed from HCMV are responsible for metabolite level changes (e.g., by targeting certain downstream enzymes).