Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• The Journal of immunology (1950), 2020-11, Vol.205 (12), p.3348-3357

Erscheinungsjahr

2020

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Relative control of HIV-1 infection has been linked to genetic and immune host factors. Herein, we analyzed 96 plasma proteome arrays from chronic-untreated HIV-1-infected individuals using the classificatory random forest approach to discriminate between uncontrolled disease (pVL>50,000 RNA copies/ml; CD4 counts 283 cells/mm 3 , n=47) and relatively controlled disease (pVL<10,000 RNA copies/ml; CD4 counts 657 cells/mm 3 , n=49). Our analysis highlighted the TNF molecules relevance, in particular, TNF-like ligand 1A (TL1A, TNFSF15) and its cognate death receptor 3 (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 non-progressors, LTNPs), thus confirming their independence from CD4 counts and pVL. Further analysis in cART-treated individuals with a wide range of CD4 counts (137–1,835 cells/mm 3 ) indicated that nor TL1A neither DR3 levels reflected recovery of CD4 counts with cART. Interestingly, in cART-treated individuals, plasma TL1A levels correlated with Tregs frequencies, while 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 , co-stimulation of PBMC with DR3-specific mAb increased the magnitude of HIV-1-specific responses. Finally, in splenocytes of DNA.HTI–vaccinated mice, co-stimulation of HTI peptides and a DR3 agonist (4C12) intensified the magnitude of T-cell responses by 27%. Our data describes for the first time the role of the TL1A-DR3 axis in natural control of HIV-1 infection and point to the use of DR3 agonists in HIV-1 vaccine regimens.