Flu Drugs Show Promise Against Cognitive Decline in HIV Patients, Preclinical Study Finds
核心洞察
Northwestern University scientists identified degradation of protective sugar molecules called glycans as a new biological mechanism linked to cognitive decline in people living with HIV (搜索).
Analysis of blood samples from more than 100 individuals with HIV (搜索) revealed a clear association between glycan degradation and cognitive impairment (搜索), with more pronounced effects observed in women.
In mouse models, sialidase inhibitors including Tamiflu (oseltamivir) preserved these sugar molecules, reduced inflammation, slowed biological aging, and protected memory function.
A class of influenza drugs known as sialidase inhibitors may hold potential for reducing cognitive decline and premature aging in people living with chronic viral infections, according to a new study led by Northwestern University researchers. The findings, published June 5 in Med, a journal from Cell Press, identify the degradation of protective sugar molecules as a previously unrecognized biological mechanism driving cognitive impairment (搜索) in people with HIV (搜索).
At least a quarter of people living with HIV (搜索) develop problems with memory and thinking, even with effective antiretroviral treatment. The reasons for these cognitive symptoms have remained unclear — until now. The Northwestern scientists identified a new biological culprit: the degradation of protective sugar molecules in the body, known as glycans, that normally help keep inflammation in check. When inflammation becomes chronic, it can accelerate biological aging by driving the immune system to overreact for too long.
"We are not saying yet that people should take flu drugs to prevent cognitive decline," explained study lead author Mohamed Abdel-Mohsen, associate professor of medicine in the division of infectious diseases at Northwestern University Feinberg School of Medicine. "We are saying that our findings open the door to testing whether this drug class, or better next-generation versions, could be repurposed for brain and aging-related complications."
Uncovering the Glycan-Cognition Link
The research team began by analyzing blood samples from more than 100 individuals with HIV (搜索) enrolled in the AIDS Clinical Trials Group. All participants were on HIV treatment and were characterized as having either normal cognition or cognitive impairment (搜索) based on clinical testing. Abdel-Mohsen's team analyzed sugar patterns on the participants' blood proteins and found a clear link between degradation of the sugar molecules and cognitive decline.
Building on this finding, the team used immune cells from people living with HIV (搜索) and mouse models with HIV to test whether the sugar degradation increased inflammation. The results confirmed that glycan breakdown contributes to the chronic inflammatory state that can damage the brain over time.
Repurposing Flu Drugs for a New Target
The flu drugs at the center of this study are called sialidase inhibitors and include Tamiflu, also known as oseltamivir. These drugs typically treat influenza by blocking a viral enzyme that helps the virus spread. In this study, however, the scientists used them differently — by blocking other enzymes in the body that degrade the protective sugar molecules.
In mouse models, the combination of Tamiflu and another experimental drug preserved the sugar molecules, reduced inflammation, slowed biological aging, and protected memory. The findings suggest that sialidase inhibitors could be repurposed beyond their antiviral indications to address the neurological complications of chronic HIV (搜索) infection, with broader implications for other aging-related diseases such as dementia (搜索).
Sex Differences in Glycan Degradation
The study also revealed notable sex-based differences. The sugar degradation was more pronounced in women. Abdel-Mohsen noted that in men, these sugar changes tend to occur gradually and steadily with aging. In women, however, the degradation starts slower and then accelerates around menopause.
"Before menopause, women show a slower loss of anti-inflammatory glycans and slower accumulation of pro-inflammatory glycans compared with men, but around menopause there is a rapid shift toward a more inflammatory glycan profile," said Abdel-Mohsen, who is also a member of Feinberg's Potocsnak Longevity Institute.
Next Steps and Cautions
Abdel-Mohsen emphasized that his team is now working on two fronts: optimizing potential treatment strategies with the flu drugs and determining whether the sugar molecules can predict future cognitive decline via new blood biomarker tests.
"On the treatment side, we want to do more preclinical work to optimize the approach. Although some sialidase inhibitors are already used safely in people for influenza, they have not been tested for this purpose, dose or duration," he said.
The study, titled "Inhibiting Glycan Degradation Prevents HIV (搜索)-Induced Inflammaging and Cognitive Impairment (搜索)," was supported by the National Institutes of Health through multiple grants and the AIDS Clinical Trials Group. Other Northwestern study authors include first author Leila Bertoni Giron and co-authors Shalini Singh and Frank Palella.