Laura Arroyo, Reben Raeman, Smita S Iyer
Immunometabolism shapes vaccine immunogenicity, yet how HIV vaccine platforms affect metabolic programs and whether those programs predict immunogenicity remain poorly understood. We applied untargeted serum metabolomics to nine rhesus macaques receiving an HIV-1 DNA-prime/protein-boost regimen, sampling at weeks 0, 1, 2, and 8 after first protein boost. Vaccination induced acute and sustained metabolic changes. Lipid metabolism showed the broadest perturbation: free fatty acids were transiently depleted during the effector phase, while acylcholines, lysophospholipids, and endocannabinoid-like ethanolamides remained elevated through week 8. Glutamate, γ-glutamyl amino acids, and glycylvaline were elevated through week 8, with continued nitrogen recycling, glutathione turnover, and proteolytic activity. High antibody responders showed greater mitochondrial fatty acid oxidation and lower bile acid levels at baseline, and greater membrane lipid remodeling at the effector phase. These data define metabolic signatures of HIV vaccination and identify serum correlates of immunogenicity for prospective validation.