Primary role of type I interferons for the induction of functionally optimal antigen-specific CD8+ T cells in HIV infectionResearch in context
Mariela P. Cabral-Piccin,
Laura Papagno,
Xavier Lahaye,
Federico Perdomo-Celis,
Stevenn Volant,
Eoghann White,
Valérie Monceaux,
Sian Llewellyn-Lacey,
Rémi Fromentin,
David A. Price,
Nicolas Chomont,
Nicolas Manel,
Asier Saez-Cirion,
Victor Appay
Affiliations
Mariela P. Cabral-Piccin
Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, 33000, Bordeaux, France; Sorbonne Université, INSERM U1135, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 75013, Paris, France
Laura Papagno
Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, 33000, Bordeaux, France; Sorbonne Université, INSERM U1135, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 75013, Paris, France
Xavier Lahaye
Institut Curie, INSERM U932, Immunity and Cancer Department, PSL Research University, 75005, Paris, France
Federico Perdomo-Celis
Institut Pasteur, Unité HIV Inflammation et Persistance, 75015, Paris, France
Stevenn Volant
Institut Pasteur, Hub Bioinformatique et Biostatistique, 75015, Paris, France
Eoghann White
Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, 33000, Bordeaux, France; Sorbonne Université, INSERM U1135, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 75013, Paris, France
Valérie Monceaux
Institut Pasteur, Unité HIV Inflammation et Persistance, 75015, Paris, France
Sian Llewellyn-Lacey
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
Rémi Fromentin
Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada
David A. Price
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK; Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK
Nicolas Chomont
Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC H2X 0A9, Canada
Nicolas Manel
Institut Curie, INSERM U932, Immunity and Cancer Department, PSL Research University, 75005, Paris, France; Corresponding author. Institut Curie, Immunity and Cancer Department, PSL Research University, 75005, Paris, France.
Asier Saez-Cirion
Institut Pasteur, Unité HIV Inflammation et Persistance, 75015, Paris, France; Institut Pasteur, Université Paris Cité, Viral Reservoirs and Immune Control Unit, 75015, Paris, France; Corresponding author. Institut Pasteur, Unité HIV Inflammation et Persistance, 75015, Paris, France.
Victor Appay
Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, 33000, Bordeaux, France; Sorbonne Université, INSERM U1135, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), 75013, Paris, France; International Research Center of Medical Sciences, Kumamoto University, Kumamoto, 860-0811, Japan; Corresponding author. Université de Bordeaux, CNRS UMR 5164, INSERM ERL 1303, ImmunoConcEpT, 33000, Bordeaux, France.
Summary: Background: CD8+ T cells equipped with a full arsenal of antiviral effector functions are critical for effective immune control of HIV-1. It has nonetheless remained unclear how best to elicit such potent cellular immune responses in the context of immunotherapy or vaccination. HIV-2 has been associated with milder disease manifestations and more commonly elicits functionally replete virus-specific CD8+ T cell responses compared with HIV-1. We aimed to learn from this immunological dichotomy and to develop informed strategies that could enhance the induction of robust CD8+ T cell responses against HIV-1. Methods: We developed an unbiased in vitro system to compare the de novo induction of antigen-specific CD8+ T cell responses after exposure to HIV-1 or HIV-2. The functional properties of primed CD8+ T cells were assessed using flow cytometry and molecular analyses of gene transcription. Findings: HIV-2 primed functionally optimal antigen-specific CD8+ T cells with enhanced survival properties more effectively than HIV-1. This superior induction process was dependent on type I interferons (IFNs) and could be mimicked via the adjuvant delivery of cyclic GMP-AMP (cGAMP), a known agonist of the stimulator of interferon genes (STING). CD8+ T cells elicited in the presence of cGAMP were polyfunctional and highly sensitive to antigen stimulation, even after priming from people living with HIV-1. Interpretation: HIV-2 primes CD8+ T cells with potent antiviral functionality by activating the cyclic GMP-AMP synthase (cGAS)/STING pathway, which results in the production of type I IFNs. This process may be amenable to therapeutic development via the use of cGAMP or other STING agonists to bolster CD8+ T cell-mediated immunity against HIV-1. Funding: This work was funded by INSERM, the Institut Curie, and the University of Bordeaux (Senior IdEx Chair) and by grants from Sidaction (17-1-AAE-11097, 17-1-FJC-11199, VIH2016126002, 20-2-AEQ-12822-2, and 22-2-AEQ-13411), the Agence Nationale de la Recherche sur le SIDA (ECTZ36691, ECTZ25472, ECTZ71745, and ECTZ118797), and the Fondation pour la Recherche Médicale (EQ U202103012774). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z).
