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Peer-reviewedCC BY 4.0Frontiers in Immunology

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

  • Jacobo Alonso-Domínguez1
  • Raquel Lama1
  • Inés Martínez-Barros1
  • Aida López-López1,2
  • Alexandre Pérez-González1,3
  • Ezequiel Ruiz-Mateos4
  • Luis F López-Cortés4
  • Iris Samarra5
  • Salvador Fernandez-Arroyo5
  • Anna Rull6,7
  • Javier Martinez-Picado7,8,9,10,11
  • Roberto Güerri-Fernández7,12,13
5 more authors
  • Mayte Coiras7,14
  • Pepa Galindo15
  • Karenina Antelo Cuéllar16
  • Víctor Asensi17
  • Eva Poveda1
17 affiliations
  1. 1Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO
  2. 2Department of Pharmacy, Complexo Hospitalario Universitario de Vigo (CHUVI), Sergas
  3. 3Internal Medicine Department, Complexo Hospitalario Universitario de Vigo (CHUVI), Sergas
  4. 4Clinical 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
  5. 5Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (Joint Unit Eurecat - Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS)
  6. 6Institut de Recerca Biomèdica Catalunya Sud, Hospital Universitari de Tarragona Joan XXIII (HJ23), Universitat Rovira i Virgili (URV)
  7. 7CIBERINFEC, Carlos III Health Institute
  8. 8Germans Trias i Pujol Research Institute, Badalona
  9. 9IrsiCaixa, Badalona
  10. 10University of Vic-Central University of Catalonia (UVic-UCC)
  11. 11Catalan Institution for Research and Advanced Studies (ICREA)
  12. 12HIV-STD Division, Group for Research in Viral Infections (GRIV), Hospital del Mar Research Institute
  13. 13Department of Medicine and Life Sciences (MELIS), Univ. Pompeu Fabra
  14. 14Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda
  15. 15Unidad de Enfermedades Infecciosas, Hospital Clínico Universitario de Valencia
  16. 16Unidad de Enfermedades Infecciosas, Hospital Universitario de Dénia
  17. 17Infectious Diseases Unit, Hospital Universitario Central de Asturias and Group of Translational Research in Infectious Diseases, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
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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.

Methods: 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.

Results: 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.

Conclusions: 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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Cite

BibTeXRIS
BibTeX
@article{alonsodominguez2026distinct,
  title = {{Distinct metabolic signatures define key HIV-1 clinical phenotypes and reveal targets beyond viral suppression}},
  author = {Jacobo Alonso-Domínguez and Raquel Lama and Inés Martínez-Barros and Aida López-López and Alexandre Pérez-González and Ezequiel Ruiz-Mateos and Luis F López-Cortés and Iris Samarra and Salvador Fernandez-Arroyo and Anna Rull and Javier Martinez-Picado and Roberto Güerri-Fernández and Mayte Coiras and Pepa Galindo and Karenina Antelo Cuéllar and Víctor Asensi and Eva Poveda},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1979386},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979386/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Distinct metabolic signatures define key HIV-1 clinical phenotypes and reveal targets beyond viral suppression
AU  - Jacobo Alonso-Domínguez
AU  - Raquel Lama
AU  - Inés Martínez-Barros
AU  - Aida López-López
AU  - Alexandre Pérez-González
AU  - Ezequiel Ruiz-Mateos
AU  - Luis F López-Cortés
AU  - Iris Samarra
AU  - Salvador Fernandez-Arroyo
AU  - Anna Rull
AU  - Javier Martinez-Picado
AU  - Roberto Güerri-Fernández
AU  - Mayte Coiras
AU  - Pepa Galindo
AU  - Karenina Antelo Cuéllar
AU  - Víctor Asensi
AU  - Eva Poveda
PY  - 2026
DA  - 2026/10/23
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1979386
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1979386/full
AB  - 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.  Methods: 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.  Results: 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.  Conclusions: 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.
SN  - 1664-3224
ER  -