Blood Glycans May Accelerate Biological Aging in HIV Patients

PHILADELPHIA, PA — The Wistar Institute’s associate professor Mohamed Abdel-Mohsen, PhD, along with his team and collaborators, has identified sugar abnormalities in the blood that may promote biological aging and inflammation in people living with HIV (PLWH). The findings, from a large data study comprising over 1,200 participants, are detailed in a new paper published in Nature Communications.

Despite advances in HIV treatment, notably the success of antiretroviral therapy (ART) in suppressing the virus to undetectable levels, HIV-AIDS remains incurable with the dormant virus persisting in the body. This chronic presence is linked to long-term health issues, including persistent inflammation and a higher prevalence of aging-related diseases, such as cancer and neurocognitive disorders. These conditions tend to occur more frequently and at an earlier age in PLWH compared to the general population. 

Abdel-Mohsen seeks to understand how chronic viral infection causes this accelerated biological aging. By understanding the molecular mechanisms behind accelerated biological aging in people living with chronic viral infections, scientists can design strategies to mitigate the negative effects.

Significance and impact of human glycome abnormalities

While many factors in the body can contribute to accelerated biological aging, researchers focused on a novel factor: abnormalities of the human glycome—the complement set of the various sugar structures circulating throughout the body. 

Previous studies have established a connection between aging and shifts in the glycan composition of immunoglobulins (IgGs), which are critical for immune regulation. As people age, their IgGs lose anti-inflammatory properties and gain pro-inflammatory characteristics. Abdel-Mohsen's research investigates whether living with a chronic viral infection, such as HIV infection, exacerbates these changes, leading to premature aging and related diseases.

By comparing glycan profiles in more than 1,200 individuals both with and without HIV, the team discovered that PLWH exhibit elevated levels of inflammatory and pro-aging IgG glycan signatures. 

Estimating biological age using machine learning

In a remarkable step forward, the team developed a machine learning (ML) model that uses these glycan signatures to estimate the biological age of PLWH and assess the rate of aging acceleration. This glycan signature also has the potential to predict the onset of comorbid conditions in PLWH, such as cancer, years in advance. 

To confirm that the glycan-associated disruptions were causal and not merely correlative, the research team engineered HIV-specific antibodies designed to exhibit the same kind of aberrant IgG glycan modifications observed in PLWH. Testing these glycoengineered antibodies in vitro confirmed that the modified antibodies were less effective at mounting an immune response than their unmodified counterparts, suggesting that these sugar abnormalities might directly contribute to adverse clinical outcomes observed. 

Importantly, when the researchers designed the antibodies to have glycans similar to those found in biologically younger individuals, these antibodies demonstrated a remarkable ability to enhance the immune system's ability to fight virus-infected cells.

"Utilizing glycan signatures to predict early onset of diseases in people living with HIV marks a pivotal shift towards proactive health care,” said Abdel-Mohsen. “This could significantly alter clinical outcomes, allowing for timely interventions and personalized treatment plans. The impact on treatment and management in the HIV community could be revolutionary. Beyond biomarkers, antibodies glycoengineered to mimic biologically younger glycans offer a new therapeutic avenue. This method could enhance immune responses, paving the way for innovative treatments.”

- This press release was originally published on The Wistar Institute website