Background
Despite early antiretroviral therapy (ART), individuals with perinatally acquired HIV often show neuroinflammation and a heightened risk of depression as they approach early adulthood. Longitudinal monitoring of inflammatory markers may provide insights into these outcomes, aiding in the prediction of neuroinflammatory processes and mental health risks. We examined these associations longitudinally in cohorts from birth to early adulthood.
Methods
Thirty-nine adolescents with HIV (56% female) from the Children with HIV Early Antiretroviral Therapy (CHER) trial were included. The median age was 16 years (IQR: 15–16), with 89.4% achieving virological suppression. Depression was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Magnetic resonance spectroscopy (MRS) measured brain metabolites (choline, myo-inositol) in the basal ganglia (BG), midfrontal gray matter (MFGM), and peritrigonal white matter (PWM). Plasma immune biomarkers (41 total) were measured at six time points: pre-ART, 1, 2, 3-4, 4-5 years post-initiation, and at 8 years. A subset was also assessed for integrase cell-associated HIV-1 DNA (iCAD), a marker of HIV-1 persistence. Correlations between biomarkers, brain metabolites, and depression scores were explored using Pearson and Spearman correlations.
Results
Pre-ART hsCRP levels positively correlated with depression scores in adolescence (r = 0.56, p < 0.01). One year post-ART, MCP-1 (CCL2) (r = -0.65, p=0.01), IL-2 (r = -0.62, p=0.02) negatively correlated with depression, while CD4 levels showed a positive correlation (r = 0.59, p=0.03). At two years, sCD163 (r = -0.57, p=0.04) and TGF-β2 (r = 0.63, p=0.02) correlated significantly, and RANTES/CCL5 (r = -0.93, p=0.02) at 4-5 years. iCAD levels correlated with YKL-40 at 16 years (r = 0.91, p=0.03). Brain metabolites pre-ART and neuroimaging at 16 years revealed Choline in the BG positively correlating with IL-17F, TNF-β, and MFGM choline. CD40L, FGF showed positive, while IL-18 and IL-8/CXCL8 showed negative relationships with immune markers. Myo-inositol exhibited similar complex associations across brain regions.
Conclusions
Our findings underscore a dynamic interaction between immune biomarkers and brain metabolites over time, linking inflammation to depression in adolescents with perinatal HIV. Early hsCRP was notably predictive of depression risk at 16 years. Further investigations, including cerebrospinal fluid biomarker analysis and advanced multi-parameter predictive models, are warranted.
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