Primary role of type I interferons for the induction of functionally optimal antigen-specific CD8+ T cells in HIV infection

Cabral-Piccin, Mariela P., Papagno, Laura, Lahaye, Xavier, Perdomo-Celis, Federico, Volant, Stevenn, White, Eoghann, Monceaux, Valérie, Llewellyn-Lacey, Sian, Fromentin, Rémi, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737, Chomont, Nicolas, Manel, Nicolas, Saez-Cirion, Asier and Appay, Victor 2023. Primary role of type I interferons for the induction of functionally optimal antigen-specific CD8+ T cells in HIV infection. EBioMedicine 91 , 104557. 10.1016/j.ebiom.2023.104557

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Abstract

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	2352-3964
Date of First Compliant Deposit:	15 May 2023
Date of Acceptance:	23 March 2023
Last Modified:	17 May 2023 06:28
URI:	https://orca.cardiff.ac.uk/id/eprint/159526

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