{ "abstract": "Introduction: 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.\n\nMethods: 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.\n\nResults: 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.\n\nConclusions: 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.", "abstract_shown": true, "affiliations": [ "Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO", "Department of Pharmacy, Complexo Hospitalario Universitario de Vigo (CHUVI), Sergas", "Internal Medicine Department, Complexo Hospitalario Universitario de Vigo (CHUVI), Sergas", "Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Institute of Biomedicine of Seville (IBiS), Virgen del Rocio University Hospital, Spanish National Research Council (CSIC), University of Seville", "Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (Joint Unit Eurecat - Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS)", "Institut de Recerca Biomèdica Catalunya Sud, Hospital Universitari de Tarragona Joan XXIII (HJ23), Universitat Rovira i Virgili (URV)", "CIBERINFEC, Carlos III Health Institute", "Germans Trias i Pujol Research Institute, Badalona", "IrsiCaixa, Badalona", "University of Vic-Central University of Catalonia (UVic-UCC)", "Catalan Institution for Research and Advanced Studies (ICREA)", "HIV-STD Division, Group for Research in Viral Infections (GRIV), Hospital del Mar Research Institute", "Department of Medicine and Life Sciences (MELIS), Univ. Pompeu Fabra", "Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda", "Unidad de Enfermedades Infecciosas, Hospital Clínico Universitario de Valencia", "Unidad de Enfermedades Infecciosas, Hospital Universitario de Dénia", "Infectious Diseases Unit, Hospital Universitario Central de Asturias and Group of Translational Research in Infectious Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)" ], "article_type": null, "arxiv": null, "author_total": 17, "authors": [ { "affs": [ 0 ], "name": "Jacobo Alonso-Domínguez" }, { "affs": [ 0 ], "name": "Raquel Lama" }, { "affs": [ 0 ], "name": "Inés Martínez-Barros" }, { "affs": [ 0, 1 ], "name": "Aida López-López" }, { "affs": [ 0, 2 ], "name": "Alexandre Pérez-González" }, { "affs": [ 3 ], "name": "Ezequiel Ruiz-Mateos" }, { "affs": [ 3 ], "name": "Luis F López-Cortés" }, { "affs": [ 4 ], "name": "Iris Samarra" }, { "affs": [ 4 ], "name": "Salvador Fernandez-Arroyo" }, { "affs": [ 5, 6 ], "name": "Anna Rull" }, { "affs": [ 6, 7, 8, 9, 10 ], "name": "Javier Martinez-Picado" }, { "affs": [ 6, 11, 12 ], "name": "Roberto Güerri-Fernández" }, { "affs": [ 6, 13 ], "name": "Mayte Coiras" }, { "affs": [ 14 ], "name": "Pepa Galindo" }, { "affs": [ 15 ], "name": "Karenina Antelo Cuéllar" }, { "affs": [ 16 ], "name": "Víctor Asensi" }, { "affs": [ 0 ], "name": "Eva Poveda" } ], "bibtex": "https://research.draconitic.com/paper/cz03sfndmpnpb.bib", "cited_by": 0, "doi": "10.3389/fimmu.2026.1979386", "fulltext_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979386/full", "id": "cz03sfndmpnpb", "issns": [ "1664-3224" ], "landing_url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979386/full", "language": "en", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "lcc", "RC581-607" ], [ "openalex", "2406|HIV Research and Treatment" ] ], "openalex": "W7223397941", "pdf_url": "https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1979386/pdf", "pmcid": null, "pmid": null, "published": "2026-10-23", "publisher": "Frontiers Media SA", "ris": "https://research.draconitic.com/paper/cz03sfndmpnpb.ris", "sources": [ { "first_seen": "2026-10-30T12:19:17Z", "native_id": "10.3389/fimmu.2026.1979386", "source": "crossref", "url": "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979386/full" }, { "first_seen": "2026-10-30T13:43:48Z", "native_id": "80c73f9cc1834145adfc78874544e295", "source": "doaj", "url": "https://doi.org/10.3389/fimmu.2026.1979386" } ], "subjects": [ { "field": "biology", "origin": "openalex:2406|HIV Research and Treatment", "subfield": "microbiology" } ], "title": "Distinct metabolic signatures define key HIV-1 clinical phenotypes and reveal targets beyond viral suppression", "title_text": "Distinct metabolic signatures define key HIV-1 clinical phenotypes and reveal targets beyond viral suppression", "type": "peer-reviewed", "updated_at": "2026-10-30T13:43:48Z", "url": "https://research.draconitic.com/paper/cz03sfndmpnpb", "venue": "Frontiers in Immunology", "versions": [] }