Recent research suggests that the loss of protective sugar molecules in the body contributes to the cognitive decline and premature aging common in people with chronic viral infections such as HIV. The findings provide evidence that a common flu drug could be repurposed to preserve these sugar molecules, a new way to protect brain health. The study was published in the journal and.
The research team was led by Northwestern University scientists, including Mohamed Abdel Mohsen, the Margaret Gray Morton Associate Professor of Medicine in the Division of Infectious Diseases at Northwestern University Feinberg School of Medicine. Abdel Mohsen is also a member of the Human Immunobiology Center, the Potokusnak Longevity Institute, and the Third Coast AIDS Research Center.
Researchers set out to understand why at least a quarter of people living with HIV have problems with memory and thinking. These cognitive problems can occur even when modern antiretroviral drugs are able to successfully control the virus in the bloodstream.
“Thanks to effective antiretroviral therapy, the lifespan of people living with HIV has increased significantly, and this has been a huge success,” Abdel Mohsen told Cypost. “However, many people still experience chronic inflammation, accelerated age-related changes, and problems with memory and thinking.” Over time, chronic viral infections can cause an ongoing low-level immune response in the body. This constant immune activity causes a biological phenomenon known as inflammation, which is a combination of chronic inflammation and accelerated biological aging.
This constant state of alertness can eventually damage healthy tissue, including the brain, and lead to cognitive problems. Scientists focused on glycans, which are complex sugar molecules attached to proteins in the blood and on cell surfaces. These sugars normally act as calming signals to the immune system and help prevent excessive inflammation.
“In our lab, we study glycans, sugar molecules that decorate cells and proteins, because they are powerful regulators of immunity and inflammation but remain often overlooked,” said Professor Abdel Mohsen. “We wanted to understand whether changes in these protective glycans could help explain why chronic viral infection continues to impact the immune system and brain, even though HIV is well controlled.”
The research team wanted to see if the loss of these specific sugars was associated with cognitive decline in people with HIV. They also wanted to test whether blocking the enzymes that break down these sugars could prevent inflammation and protect memory. The enzyme that removes these sugars is called sialidase. Interestingly, common flu drugs are actually sialidase inhibitors, meaning they are designed to block this very type of enzyme to stop the spread of the influenza virus.
To explore this link, the scientists first analyzed blood samples from a long-term health tracking project. They tested a group of 40 people with HIV who were taking effective antiviral drugs. Twenty of these participants were male and 20 were female. Half of the group had been formally diagnosed with cognitive impairment, while the other half had normal cognitive function based on standard laboratory tests.
The researchers followed these people for eight years, collecting five to nine blood samples from each person. They used special laboratory techniques to measure specific types of sugar molecules that bind to immune proteins in the blood. The results showed that participants with cognitive impairment had greater sustained loss of protective sugars compared to participants with normal memory function. This loss was directly correlated with lower scores on cognitive tests.
“In our study, we found that the breakdown of protective glycans that normally protect the body from excessive inflammation, but which are normally lost with age, was broken down at a faster rate in people with HIV and cognitive impairment, especially women, than normal for their age,” Abdelmohsen explained.
The scientists then tested these findings in another cross-sectional group of 80 people with HIV. The validation group also included 40 men and 40 women, evenly split between those with and without cognitive impairment. The researchers found similar patterns of glycolysis in the impaired group.
They also measured standard inflammatory markers in the blood, but found that sugar breakdown was a much more accurate indicator of cognitive problems than underlying inflammation. Interestingly, the loss of these protective sugars was more pronounced in women than in men. Women with cognitive impairment showed much higher losses of sialic acid and galactose than women without cognitive impairment.
Scientists suggest that this difference may be related to hormonal changes over a person’s lifetime. In women, the breakdown of sugar tends to accelerate around menopause, which can create a period when the brain is more vulnerable. “We were also struck by the stronger glycan signal in women, suggesting that gender, hormonal biology, and menopause may be important components of this pathway,” Abdelmohsen said.
Following the human data, the research team conducted experiments using human immune cells to see if they could stop the damage. They exposed the immune cells to sialidase, an enzyme that naturally removes sialic acid. As expected, this exposure triggered a strong inflammatory response and the release of harmful chemicals from the cells. The researchers then treated the cells with a sialidase inhibitor. Sialidase inhibitors are a class of drugs that includes the common influenza drug oseltamivir, commercially known as Tamiflu.
They combined oseltamivir with an experimental drug called DANA. This combination prevented the loss of protective sugars. As a result, the cells stopped releasing inflammatory signals and remained calm and healthy. To test this approach in a living system, the scientists used a special model of mice that had been biologically modified to have human immune cells.
They infected these humanized mice with HIV and gave half of them a combination of influenza drugs orally every day. The researchers tracked the mice’s immune health and virus levels for five weeks and compared them to untreated infected mice and healthy, uninfected mice. Untreated mice developed high levels of systemic inflammation and showed signs of accelerated epigenetic aging. Epigenetic aging refers to chemical modifications of DNA that change the way genes are expressed, which act as the body’s biological clock.
Mice treated with influenza drugs had significantly less inflammation and immune system depletion. Daily treatment also prevented the accelerated epigenetic aging seen in untreated animals. Because that particular humanized mouse model cannot be used for complex behavioral tests, the authors turned to a second animal model. They infected standard laboratory mice with a modified form of HIV specifically designed to infect mouse cells.
Twenty-five days after the initial infection, the researchers began treating some of the mice with a combination of influenza drugs using a daily nasal spray for 10 days. The scientists then tested the animals’ spatial learning and memory using a radial arm water maze. This test requires mice to swim and find a hidden platform within a pool of water over several days of training trials. Untreated infected mice made significantly more errors and had a harder time remembering the platform position from day to day.
In contrast, mice treated with influenza drugs performed similarly to uninfected healthy mice. This treatment completely prevented memory loss caused by the virus. The researchers also examined the brain tissue of these animals after the behavioral tests were completed to understand what was happening at the cellular level. They found that drug treatment stores protective sialic acid sugars directly in the brain.
Treated brains showed a reduction in neuroinflammatory markers and normalization of gene expression. Additionally, the treatment prevented the accumulation of proteins commonly associated with neurodegeneration, such as amyloid and tau proteins, which are often involved in dementia.
“One of the surprising aspects was that the different parts of the study were very well put together,” Abdel Mohsen said. “We started with glycan patterns in blood samples from people with HIV, then tested the mechanism in cells and animal models, and found that protecting these glycans could reduce inflammation and cognitive problems in mice.”
“Importantly, when we looked at animal models to prevent these glycans from being degraded using the types of drugs typically used to treat influenza, we found that inflammation, age-related changes, and memory impairment were reduced,” Abdelmohsen added. “This suggests new mechanisms and future therapeutic directions.”
“The main message is that sugar molecules in the body are not just passive decorations, but can actively regulate inflammation, aging-related biology, and possibly brain health.”
Although these findings provide evidence for new therapeutic approaches, there are several limitations that should be considered. Sample sizes in human observational studies were relatively small. Because all of the HIV-infected participants were already taking effective antiviral drugs, it is unclear how these sugar changes work in untreated individuals. Large observational studies that follow individuals before and after cognitive problems develop will be needed to determine whether changes in these sugars can reliably predict future memory decline.
“While the human part of the study shows an association between glycolysis and cognitive impairment, this in itself does not prove that glycolysis causes cognitive decline in people,” Abdel Mohsen said. “Therapeutic efficacy was shown in preclinical models and not in human clinical trials.”
“Also, some sialidase inhibitors are already in clinical use against influenza, but they have not been tested for this purpose, dose, duration, or long-term safety,” he continued. “Based on this study, people should not take flu drugs for memory loss,” he reiterated, “but it is very important to emphasize that this is not a recommendation for people to take flu drugs to prevent or treat memory loss.” Future research will focus on developing better drugs that specifically target the enzymes involved in human glycolysis.
Scientists also plan to investigate exactly how sex hormones, such as estrogen, affect the production and loss of these protective sugar molecules. Expanding this research could ultimately lead to new treatments to protect the brain during long-term viral infections and other age-related diseases.
“Our next goals are to better understand how these protective glycans are lost during chronic HIV infection and aging, to optimize strategies to preserve them, and to determine whether glycan-based blood biomarkers can predict who is at risk for future cognitive decline and other aging-related complications,” Abdelmohsen said. “We also want to develop safer and more targeted approaches, which may or may not be the same drugs currently used for influenza.”
“The ultimate goal is to move from understanding this mechanism to designing clinical studies to test safety, targeting, and ultimately whether this approach can improve healthspan in people with HIV infection and perhaps a broader range of aging-related diseases,” he said. “I think this study highlights a broader point: As people with HIV live longer, the next big challenge is not only to protect lifespan, but also to protect healthy lifespan.”
“We need to understand why chronic inflammation and age-related complications persist despite excellent antiviral therapies. Glycans may provide a new window into their biology, which could ultimately help develop new diagnostics and treatments.”
“Inhibition of glycan degradation The authors of the study, “Preventing Induced Inflammation and Cognitive Impairment,” are Leila B. Gillon, Alejandra Borjavado, Elan Hadas, Janeway Grandche, Erica G. Marquez de Menezes, Thomas A. Premaux, Hongxia He, Stephen T. Yong, Shalini Singh, Courtney Friday, Joshua Glover, and Rick Balboa, Derrick Dopkin, Michelle Burrows, Anthony Secreto, Nicholas Skuri, Hiroaki Tateno, Paul W. Denton, Frank Parella, Michael J. Corey, Rishomwa C. Ndlovu, Philip J. Norris, Catherine Tasiopoulos, David J. Volski, Mohamed Abdel-Mohsen.
