This 2021 study from the University of Birmingham dug deeper into a question the earlier Fox et al. (2010) paper raised: if the immune system can detect EBV-infected cells, why doesn't it clear them? The answer researchers found points to a previously overlooked culprit — a type of immune cell that actively suppresses the body's own defenses.

The team developed a new lab technique called FlowRNA, which combines cell-marker staining with direct detection of the virus's genetic signature inside individual cells. This let them pinpoint exactly which immune cells EBV was hiding in in five adult patients with CAEBV (chronic active EBV infection) or EBV-HLH, and study how those infected cells behaved compared to uninfected ones.

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What they found:

• EBV infected different cell types in different patients — B cells in two patients, T cells in two others, and in one patient, the virus was found in NK cells, T cells, and B cells simultaneously.
• Infected T cells showed clear signs of activation and rapid proliferation, and in several patients formed a single dominant "clone" — essentially one infected cell multiplying out of control.
• Even after treatment appeared to resolve symptoms, EBV-infected cells often persisted or rebounded — in one patient, the exact same infected cell clone reappeared and caused a fatal relapse nearly two years after a stem cell transplant.
• Crucially, the researchers discovered that patients had large numbers of myeloid-derived suppressor cells (MDSCs) circulating in their blood — cells known to shut down healthy T-cell activity. In lab tests, these MDSCs strongly suppressed T-cell growth, suggesting they may be disarming the very immune cells that should be clearing the virus.
• Patients' blood also contained elevated levels of specific inflammatory signals (including GM-CSF, IL-6, and arginase-1) known to help these suppressor cells multiply and function.

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Why it matters:

This research offers a possible explanation for why EBV-HLH and CAEBV are so difficult to treat: it isn't just that the virus hides in immune cells, but that it may also trigger the expansion of cells that block the body's ability to fight back. Standard treatments like corticosteroids, which suppress T-cell activity, may inadvertently make this worse. The findings point toward a future where treatment could target these suppressor cells directly, offering a more effective approach than the current reliance on stem cell transplantation.

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