Flu drugs may help ward off the low-grade inflammation and related cognitive decline that can come with HIV infection, an early study suggests.

Upwards of 24% of people with HIV experience some degree of cognitive impairment that interferes with functions like attention, concentration and multitasking. These declines are often mild but can worsen quality of life, and they can happen even when a person consistently takes HIV medications that suppress the virus.

Understanding why this impairment emerges and how to prevent it is especially relevant as the population of people with HIV grows older.

"This is very important," study co-author Mohamed Abdel-Mohsen, an associate professor of medicine in the division of infectious diseases at Northwestern University Feinberg School of Medicine. "Despite the fact that people living with HIV live longer, so the lifespan is preserved, the 'health span' is not as preserved."

The new study, published Friday (June 5) in the journal Med, pinpoints a potential driver of this decline along with a strategy to reverse it. The scientists used mouse experiments and blood samples from HIV patients, so the work is at an early stage, but it could open the door to future treatments.

"Not only do they describe a mechanism, but they then report in animal models that this mechanism is something that potentially could be targeted by an intervention," said Dr. Alan Winston, a professor of HIV and genitourinary medicine at Imperial College and a consultant physician at St. Mary's Hospital in London. "That's really what's novel," said Winston, who was not involved in the study.

Anti-inflammatory sugars

HIV treatments are now so effective that people with the chronic viral infection can live nearly as long as people without HIV, provided they consistently take the medicines. In 2022 in the U.S., more than half of people living with HIV were over 50 years old, and that figure is expected to grow.

HIV treatment, called antiretroviral therapy (ART), suppresses the virus so that it can't multiply. This prevents the disease from progressing to AIDS while also driving down transmission rates, making the virus unable to spread via sex. But while ART wards off many symptoms of HIV/AIDS and extends an infected person's lifespan, it does not make the chronic infection completely benign. People with HIV still show various signs of accelerated aging, including earlier cognitive decline, in some cases.

"Before we had antiretroviral therapy, we saw profound effects of HIV in the brain," Winston noted. HIV-associated dementia is now rare, because its rates declined as the use of ART increased.

But some percentage of people still develop milder cognitive impairments, and "it can actually have quite a big impact on concentrating at work, for instance, and undertaking daily activities," he said. People have a higher risk of impairment when they've had a big gap between contracting HIV and starting ART, and interruptions in treatment can also raise the risk. However, the underlying cause of the impairments isn't fully understood, Winston said.

To unpack that mechanism, Abdel-Mohsen and colleagues investigated a clue that's recently emerged in the medical literature: sugar molecules called glycans.

These sugars are found throughout the body, including in the bloodstream, where they bind to proteins and fats. In circulation, they tag certain immune molecules to keep inflammation in check. But with age, the concentration of these inflammation-controlling glycans declines: This decline is fairly steady for males, while it has a sudden dip around menopause for females, Abdel-Mohsen said.

Scientists have previously explored how this decline might contribute to age-related diseases, including cancer, while Abdel-Mohsen and colleagues have investigated its relationship to HIV. In a 2024 study comparing people with and without HIV, they found that those with the infection show age-related shifts in their glycans at younger ages than usual. These shifts come with an increase in enzymes known to degrade the sugars, as well as increases in inflammation.

"While it's low-grade [inflammation], it's still damaging because it's continuous," Abdel-Mohsen said. "It's chronic; it doesn't get resolved."

Potential treatment?

In their latest study, the researchers wanted to see if they could connect the dots between the glycan loss, inflammation and cognitive decline.

They analyzed blood samples from more than 100 people with HIV who contributed data to the AIDS Clinical Trials Group, a global research network. All the individuals were taking ART and either had signs of cognitive impairment or did not, according to various assessments. The group with impairments showed greater losses in two glycans that help control inflammation: sialic acid and galactose. In particular, these losses were most pronounced in women, and they correlated with the degree of cognitive decline seen in a given person.

It's not clear why this pattern was more pronounced in women, and that remains a question for future study, Abdel-Mohsen noted. That said, it's known that glycans dip around menopause and that key immune cells bear estrogen receptors, so it's possible that estrogen levels play a role, he suggested. Winston wondered if the timing of diagnosis might also be relevant, since women tend to get diagnosed later than men and may therefore start ART later.

After studying the blood samples, the team used two models of HIV infection in lab mice. One enabled them to study the glycan changes and inflammation triggered by HIV, while the second let them examine signs of cognitive decline. They again found that infection was tied to a loss of glycans and increase in inflammation, as well as worse performance on cognitive tests.

Next, they set out to see if they could reverse those effects.

A class of drugs called sialidase inhibitors work by blocking the effects of enzymes that split sialic acid, one of the key inflammation-quenching glycans. These drugs include Tamiflu, because flu viruses rely on sialic acid to infect cells and spread through the body. The team found that, at least in mice, these flu drugs helped preserve sialic acid, prevent inflammation and improve cognition.

We saw that "this class of inhibitor could reduce inflammation caused by viral infection … and even more importantly, preserve cognition and and prevent memory deficits," Abdel-Mohsen said.

Abdel-Mohsen considers this work "proof-of-concept" that glycans may play a role in HIV-related cognitive decline, pointing to potential treatments. The end goal isn't necessarily to use flu drugs to treat cognitive impairment in HIV, but rather to identify compounds that could "either prevent the glycans from being degraded or just replace them," he said.

One limitation of the current study is that its definition of cognitive impairment was limited, Winston noted. It relied on cognitive test scores — how well participants solved various puzzles — and a standard "scoring" system that's used to assess a handful of cognitive functions. Including details of patients' symptoms and challenges they experience in daily life would have made the meaning of those scores more tangible, Winston said, and he would hope to see that in future work.

In the long run, Winston could see this research leading to a "precision medicine" approach in which patients' glycan levels are checked, and if they're low, they could get a treatment to address that. It's likely that different factors drive cognitive impairment in different people with HIV, so matching patients with the right treatment is imperative, he said.

And in theory, it may be that the loss of glycans also drives other issues seen in aging adults with HIV, such as increased rates of cardiovascular disease. If that's the case, the same treatments may serve multiple functions. "It will be definitely fantastic to study and see how targeting this mechanism could impact the multiple comorbidities," Abdel-Mohsen said.