Distinct metabolic signatures define key HIV-1 clinical phenotypes and reveal targets beyond viral suppression.

Abstract

Despite effective antiretroviral therapy (ART), metabolic dysfunction persists in people with HIV (PWH) and may contribute to immune dysregulation and non-AIDS comorbidities. However, the metabolomic profiles associated with untreated infection, immune recovery, immune non-response, and spontaneous viral control remain incompletely defined. Plasma metabolomics was performed in 140 participants: HIV-negative controls (n=30), treatment-naive individuals (n=30), ART-treated immune responders (IR; n=30), immune non-responders (INR; n=20), and elite controllers (n=30), subdivided into persistent (PC; n=15) and transient controllers (TC; n=15). Targeted and semi-targeted LC-MS and GC-MS analyses were combined with differential metabolite, over-representation, and quantitative enrichment analyses. The extent of metabolic disruption differed markedly across phenotypes. Treatment-naive individuals showed 142 altered metabolites, followed by INR (114), TC (68), and PC (28), whereas IR showed only 4. Untreated infection was characterized by sphingolipid depletion, triglyceride accumulation, and mitochondrial pathway alterations. Despite comparable ART exposure, INR retained pronounced eicosanoid, amino acid, and energy metabolism abnormalities, whereas IR exhibited near-normalization, indicating that residual dysfunction was associated with impaired immune reconstitution rather than ART itself. Elite controllers displayed distinct metabolic adaptations: PC showed increased acylcarnitines and enrichment of pyruvate metabolism, the urea cycle, and the Warburg effect, whereas TC exhibited broader carbon and nitrogen metabolic perturbations before loss of spontaneous viral control. Arachidonic acid metabolism remained altered across all HIV phenotypes. Distinct metabolomic signatures characterize the major viroimmunological phenotypes of HIV infection. Effective ART combined with immune reconstitution was associated with metabolic normalization, while spontaneous viral control revealed pathways potentially relevant to immunological stability.

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