TL1A-DR3 plasma levels are predictive of HIV-1 disease control, and DR3 costimulation boosts HIV-1-specific T cell responses

Bruna Oriol-Tordera, Alex Olvera, Clara Duran-Castells, Anuska Llano, Beatriz Mothe, Marta Massanella, Judith Dalmau, Carmela Ganoza, Jorge Sanchez, Maria Luz Calle, Bonaventura Clotet, Javier Martinez-Picado, Eugénia Negredo, Juliá Blanco, Dennis Hartigan-O'Connor, Christian Brander, Marta Ruiz-Riol

Research output: Contribution to journalArticlepeer-review


Relative control of HIV-1 infection has been linked to genetic and immune host factors. In this study, we analyzed 96 plasma proteome arrays from chronic untreated HIV-1-infected individuals using the classificatory random forest approach to discriminate between uncontrolled disease (plasma viral load [pVL] >50,000 RNA copies/ml; CD4 counts 283 cells/mm3, n = 47) and relatively controlled disease (pVL <10,000 RNA copies/ml; CD4 counts 657 cells/mm3, n = 49). Our analysis highlighted the TNF molecule's relevance, in particular, TL1A (TNFSF15) and its cognate DR3 (TNFSRF25), both of which increased in the relative virus control phenotype. DR3 levels (in plasma and PBMCs) were validated in unrelated cohorts (including long-term nonprogressors), thus confirming their independence from CD4 counts and pVL. Further analysis in combined antiretroviral treatment (cART)-treated individuals with a wide range of CD4 counts (137-1835 cells/mm3) indicated that neither TL1A nor DR3 levels reflected recovery of CD4 counts with cART. Interestingly, in cART-treated individuals, plasma TL1A levels correlated with regulatory T cell frequencies, whereas soluble DR3 was strongly associated with the abundance of effector HLA-DR+CD8+ T cells. A positive correlation was also observed between plasma DR3 levels and the HIV-1-specific T cell responses. In vitro, costimulation of PBMC with DR3-specific mAb increased the magnitude of HIV-1-specific responses. Finally, in splenocytes of DNA.HTI-vaccinated mice, costimulation of HTI peptides and a DR3 agonist (4C12) intensified the magnitude of T cell responses by 27%. These data describe the role of the TL1A-DR3 axis in the natural control of HIV-1 infection and point to the use of DR3 agonists in HIV-1 vaccine regimens.

Original languageEnglish (US)
Pages (from-to)3348-3357
Number of pages10
JournalJournal of Immunology
Issue number12
StatePublished - Dec 15 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


Dive into the research topics of 'TL1A-DR3 plasma levels are predictive of HIV-1 disease control, and DR3 costimulation boosts HIV-1-specific T cell responses'. Together they form a unique fingerprint.

Cite this