HTLV-1 is a cancer-causing retrovirus known to lead to adult T-cell leukemia/lymphoma (ATL), an aggressive and often fatal disease. Although most infected individuals remain asymptomatic for life, a fraction eventually develops leukemia or other inflammatory conditions. The virus achieves long-term persistence by entering a "latent" state, during which its genetic material hides inside the host's genome with minimal activity -- evading immune detection.

In this study, the research team, led by Professor Yorifumi Satou from the Joint Research Center for Human Retrovirus, Kumamoto University, identified a specific region within the HTLV-1 genome that functions as a viral silencer. This sequence recruits host transcription factors, particularly the RUNX1 complex, which suppresses the virus's gene expression. When this silencer region was removed or mutated, the virus became more active, leading to greater immune recognition and clearance in lab models.

Remarkably, when the HTLV-1 silencer was artificially inserted into HIV-1 -- the virus that causes AIDS -- the HIV virus adopted a more latent-like state, with reduced replication and cell killing. This suggests that the silencer mechanism could potentially be harnessed to design better therapies for HIV as well.

"This is the first time we've uncovered a built-in mechanism that allows a human leukemia virus to regulate its own invisibility," said Professor Satou. "It's a clever evolutionary tactic, and now that we understand it, we might be able to turn the tables in treatment."

The findings offer hope not only for understanding and treating HTLV-1, especially in endemic regions like southwestern Japan, but also for broader retroviral infections.

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Published on August 1 in JAMA Network Open, the study analyzed the health records of more than 12,000 people in British Columbia and found that those with MS began using healthcare services at elevated rates 15 years before their first MS symptoms appear.

The findings challenge long-held assumptions about when the disease truly begins, offering the most comprehensive picture to date of how patients engage with a range of healthcare providers in the years leading up to a diagnosis as they search for answers to ill-defined medical challenges.

"MS can be difficult to recognize as many of the earliest signs -- like fatigue, headache, pain and mental health concerns -- can be quite general and easily mistaken for other conditions," said senior author Dr. Helen Tremlett, professor of neurology at UBC's faculty of medicine and investigator at the Djavad Mowafaghian Centre for Brain Health. "Our findings dramatically shift the timeline for when these early warning signs are thought to begin, potentially opening the door to opportunities for earlier detection and intervention."

The study used linked clinical and administrative provincial health data to track physician visits in the 25 years leading up to the onset of a patient's MS symptoms, as determined by a neurologist through detailed medical history and clinical assessments.

It is the first study to examine healthcare usage this far back in a patient's clinical history. Most previous studies only examined trends in the five to 10 years leading up to a patient's first demyelinating event (such as vision problems) using administrative data. This is a much later benchmark compared to the neurologist-determined date of symptom onset.

The findings revealed that, when compared to the general population, people with MS had a steady build-up of healthcare engagement over 15 years with different types of doctor visits increasing at distinct points in time:

• 15 years before symptom onset: Visits to general practice physicians increased, as did visits to any physician for symptoms like fatigue, pain, dizziness and mental health conditions including anxiety and depression.
• 12 years before: Visits to a psychiatrist increased.
• Eight to nine years before: Visits to neurologists and ophthalmologists increased, which could relate to issues like blurry vision or eye pain.
• Three to five years before: Emergency medicine and radiology visits increased.
• One year before: Physician visits across multiple specialties peaked, including neurology, emergency medicine and radiology.

"These patterns suggest that MS has a long and complex prodromal phase -- where something is happening beneath the surface but hasn't yet declared itself as MS," said Dr. Marta Ruiz-Algueró, a postdoctoral fellow at UBC and the study's first author. "We're only now starting to understand what these early warning signs are, with mental health-related issues appearing to be among the earliest indicators."

The study builds on previous work by Dr. Tremlett and her team to characterize the early stages of MS, or prodromal phase, when subtle symptoms appear before the hallmark signs become recognizable. Prodromal periods are well established in other neurological disorders, like Parkinson's disease, where mood changes, sleep disturbances and constipation often arise years before the more familiar motor symptoms like tremors and stiffness.

While the researchers caution that the vast majority of people who experience general symptoms will not go on to develop MS, they say recognizing and characterizing the MS prodrome could one day help accelerate diagnosis and improve outcomes for patients.

"By identifying these earlier red flags, we may eventually be able to intervene sooner -- whether that's through monitoring, support or preventive strategies," said Dr. Tremlett. "It opens new avenues for research into early biomarkers, lifestyle factors and other potential triggers that may be at play during this previously overlooked phase of the disease."