Toll-like receptor agonists enhance HIV-specific T cell response mediated by plasmacytoid dendritic cells in diverse HIV-1 disease progression phenotypesResearch in context
Maria R. Jimenez-Leon,
Carmen Gasca-Capote,
Laura Tarancon-Diez,
Beatriz Dominguez-Molina,
Macarena Lopez-Verdugo,
Ryan Ritraj,
Isabel Gallego,
Ana I. Alvarez-Rios,
Joana Vitalle,
Sara Bachiller,
María Inés Camacho-Sojo,
Alberto Perez-Gomez,
Nuria Espinosa,
Cristina Roca-Oporto,
Mohamed Rafii-El-Idrissi Benhnia,
Alicia Gutierrez-Valencia,
Luis F. Lopez-Cortes,
Ezequiel Ruiz-Mateos
Affiliations
Maria R. Jimenez-Leon
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Carmen Gasca-Capote
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Laura Tarancon-Diez
Immunology Section, Laboratorio InmunoBiología Molecular (LIBM), Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Area of Immune System Pathology, Madrid, Spain
Beatriz Dominguez-Molina
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Macarena Lopez-Verdugo
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Ryan Ritraj
Harvard Medical School, Boston, MA, USA
Isabel Gallego
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Ana I. Alvarez-Rios
Department of Clinical Biochemistry, Virgen del Rocío University Hospital, CSIC, University of Seville, Seville, Spain
Joana Vitalle
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Sara Bachiller
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
María Inés Camacho-Sojo
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Alberto Perez-Gomez
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Nuria Espinosa
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Cristina Roca-Oporto
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Mohamed Rafii-El-Idrissi Benhnia
Department of Medical Biochemistry, Molecular Biology, and Immunology, School of Medicine, University of Seville, Seville, Spain
Alicia Gutierrez-Valencia
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Luis F. Lopez-Cortes
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain
Ezequiel Ruiz-Mateos
Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Clinical Unit of Infectious Diseases, Microbiology and Parasitology, Seville, Spain; Corresponding author. Laboratory of Immunovirology (Lab 211), Biomedicine Institute of Seville (IBIS), Virgen del Rocío University Hospital, Avda. Manuel Siurot s/n., CP 41013, Seville, Spain.
Summary: Background: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. Methods: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. Findings: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. Interpretation: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. Funding: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, “a way to make Europe”) and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).
