Understanding the contribution of the glycome and specific plasma glycoproteins to the onset of non-communicable diseases in people with HIV

HIV remains a common, chronic infection globally, with around 39 million people living with the virus by the end of 20221. The aging HIV population is due to improved life expectancy with effective antiretroviral therapy (ART) and new HIV diagnoses in older adults2. This aging increases the risk of age-related non-communicable diseases (NCD) among people with HIV3.

NCDs are associated with high mortality, increasing multimorbidity rates, substantial healthcare costs, and reduced quality of life4,5. While traditional risk factors like smoking and obesity contribute to NCD prevalence6, host inflammation plays a significant role in the increased risk7.

Host inflammation is complex and influenced by lifestyle, demographics, HIV infection, and associated immunodeficiency8. However, not all people with HIV exhibit the same inflammatory profile, indicating the potential for personalized medicine and interventions based on host biological and molecular data9. Glycans, critical components of surface and secreted proteins, have been studied for their impact on inflammation10.

Research has identified glycomic profiles predictive of cardiovascular disease (CVD) events in people with HIV11,12, suggesting glycan biomarkers as potential tools for identifying those at higher NCD risk.

To explore this further, the project will analyze samples and data from two established HIV cohorts in the UK and Ireland: the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) cohort and the All Ireland Infectious Diseases (AIID) Cohort. The study will perform plasma N-Glycome analysis in people with key NCDs (CVD, diabetes, chronic respiratory disease, mental health problems) and controls without NCD.

The goal is to identify candidate plasma glycoproteins contributing to changes in plasma and conduct specific anti-HIV antibody glycome analysis. This involves treating plasma samples with PNGaseF to release glycans, labeling, and running them on a LC HILIC column with fluorescence detection (FD) and online mass spectrometry (MS)13. Data integration with Happy Tools (FD) and LacyTools (MS) will enable statistical analysis to assess the independent contribution of the glycome to NCD development relative to established risk factors.

Additionally, the project will characterize total IgG Fc glycosylation in a subset of individuals by isolating circulating IgG and performing glycan release, labeling, and HILIC-FD-MS14. The aim is to identify a glycosignature of IgG Fc that correlates closely with major NCD. If time allows, a detailed nanoLC-ESI-MS analysis will be conducted on paired plasma samples representing participants with incident NCD and those without, matched by age and sex.

This project has the potential to advance our understanding of NCD development in people with HIV and pave the way for personalized approaches to prevent and manage these diseases. The utilization of glycan biomarkers in the context of HIV and NCDs could have significant implications for improving patient outcomes and healthcare strategies15.