The immunological, biochemical and molecular mechanisms associated with poor immune recovery are far from known, and metabolomics profiling offers an additional value to traditional soluble markers. Here, we search for predictive markers of late immune response and disease progression in a cohort of HIV-subjects with increased CD4 T-cell turnover and inflammation preceding their poor immune recovery.
We executed a nuclear magnetic resonance (NMR) and mass spectrometry (MS)-based circulating metabolomics approach in 41 cART-naive HIV-infected patients who were initiating cART and subsequently followed up these patients for 96 weeks (n = 17). Random forest (RF) was performed to identify the variables that best partitioned the overall study population according to immune recovery predisposition. Network of metabolite-protein interaction and functional enrichment analyses were generated to identify the metabolomics pathways affected.
Plasma L-tyrosine (P = 0.04), L-glutamate (P = 0.05), and phosphatidylcholine (PC) (16:1) (P = 0.01) by univariate model, and hsCRP, IL-6 and palmitoylcarnitine (PalC) by Random Forest, were identified as predictive markers of late immune recovery. After 96 weeks of cART, CD4+ T-cell counts were positively correlated to glycocholic acid (r = 0.51, P = 0.04) and citrulline (r = 0.60, P = 0.03), and inversely correlated to lipopolysaccharide (LPS) (r = -0.61, P = 0.03) and DL-pipecolic acid (r = -0.94, P < 0.01). Compositional and structural changes on HDL and decreased glutamate concentrations were associated to immune recovery during cART.
Metabolomics improve the value of soluble parameters and shows novel and relevant data that may contribute to a better understanding of molecular mechanisms preceding discordant response and immunological progression under suppressive stable cART. The metabolomics signature of ART-naïve HIV subjects with late immune recovery is the expression of pro-inflammatory molecules and glutaminolysis, which is probably related to their higher T-cell turnover.