PROJECT SUMMARY: There is an urgent need to identify biomarkers that can predict the development of inflammation-associated comorbidities in people with HIV (PWH) on antiretroviral therapy (ART), as well as to develop novel strategies to prevent or treat these comorbidities. Our recent data suggest that glycomic alterations in circulating IgGs are not only candidates for such biomarkers but they may also mechanistically contribute to HIV-associated inflammation by compromising antiviral immuity in a manner that can be normalized In the general population, IgG glycomic alterations drive inflammatory responses during aging (inflammaging). In a recent publication (Giron et al., Nature Communications, 2024), we found that living with ART-suppressed HIV infection is associated with an acceleration in the accumulation of pro-aging IgG glycomic alterations. Specifically, antibodies from PWH on ART showed a significant loss of the anti-inflammatory glycans galactose (agalactosylation) and sialic acid (hypo-sialylation) compared to HIV-negative controls. These alterations were associated with greater inflammation and increased severity of inflammaging-associated comorbidities in PWH on ART. In proof-of-concept studies, we also found that these alterations might precede the development of such comorbidities by years, making them viable candidates for discovering predicitive biomarkers. Beyond their potential as biomarkers, agalactosylation and hypo-sialylation could also constitute causative mechanisms contributing to inflammation in PWH on ART: 1) Agalactosylation: Glycans on IgGs regulate the binding of IgGs to their Fc receptors, defining the ability of IgGs to elicit anti-viral innate immune functions. We examined whether the lack of galactose on IgGs compromised their anti-HIV Fc-mediated immune functions; we glyco-engineered the HIV antibody 10-1074 to produce agalactosylated and highly-galactosylated glycoforms. Agalactosylated glycoforms exhibited significantly lower