Inhibiting glycan degradation prevents HIV-induced inflammaging and cognitive impairment

Cognitive impairment is a frequent outcome of chronic viral infections linked to premature aging, including HIV. The mechanisms underlying this decline remain poorly understood. Here, we identify pro-inflammatory glycan degradation, characterized by loss of sialic acid and galactose, both hallmarks of premature aging, as a key contributor to HIV-associated cognitive impairment (HIV-CI).

We analyzed two cohorts of people with HIV, with and without HIV-CI, and tested causality through intervention studies in two complemetary mouse models of virally mediated inflammation and cognitive deceline.

Degradative glycomic changes were enriched in people with HIV with cognitive impairment, particularly females, and correlated with worse cognitive performance. In both a humanized mouse model of HIV and EcoHIV model, a complementary model that enables cognitive testing, pharmacological inhibition of glycan degradation with sialidase inhibitors prevented virally induced inflammation, immune activation, accelerated aging, and memory deficits.

These findings implicate glycan degradation as a contributor to inflammation and cognitive impairment in HIV and highlight glycan preservation as a promising strategy to mitigate inflammation, premature aging, and cognitive decline during viral infections.

This study was funded by the National Institutes of Health (NIH).