LAUSR

OBJECTIVE HIV cure research urgently needs to identify pre-Analytic Treatment Interruption (ATI) biomarkers of time-to-viral-rebound and viral setpoint to mitigate the risk of ATI and accelerate development of a cure. We previously reported that galactosylated IgG glycans, G2, negatively correlate with cell-associated HIV DNA and RNA during antiretroviral therapy (ART). We hypothesized that this and other plasma glycomic traits can predict time-to-viral-rebound and viral setpoint upon ART cessation. DESIGN We profiled the circulating glycomes (plasma and bulk IgG) of two geographically-distinct cohorts: (1) Philadelphia Cohort - 24 HIV-infected, ART-suppressed individuals who had participated in an open-ended ATI study without concurrent immunomodulatory agents. (2) Johannesburg Cohort - 23 HIV-infected, ART-suppressed individuals who had participated in a two-week ATI. METHODS Capillary electrophoresis and lectin microarray were used for glycomic analyses. Cox proportional-hazards model and log-rank test were used for statistical analyses. RESULTS Higher pre-ATI levels of the IgG glycan, G2, were significantly associated with a longer time-to-viral-rebound (hazard ratio (HR) = 0.12, P = 0.05). In addition to G2, we identified several predictive glycomic traits in plasma, e.g., levels of FA2BG1, a non-sialylated, core-fucosylated glycan, associated with a longer time-to-viral-rebound (HR = 0.023, P = 0.05), whereas FA2G2S1, a sialylated glycan, associated with a shorter time-to-viral-rebound (HR = 24.1, P = 0.028). Additionally, pre-ATI plasma glycomic signatures associated with lower viral setpoint, e.g., T-antigen (Galβ1-3GalNAc) (r = 0.75, P = 0.0007), or higher viral setpoint, e.g., polylactosamine (r = -0.58, P = 0.01). These results were initially validated in the Johannesburg Cohort. CONCLUSIONS We describe first-in-class, non-invasive, plasma and IgG glycomic biomarkers that inform time-to-viral-rebound and viral setpoint in two geographically-distinct cohorts.