Thursday Seminar: Victor Appay

“Induction of functionally optimal antigen specific CD8+ T cells in HIV infection”: CD8+ T cells with optimal functional attributes play a key role in the control of HIV infection. However, their induction in the setting of anti-HIV-1 therapeutic approaches remains a challenge. HIV-2 is associated with milder disease manifestations than HIV-1 and the presence of qualitatively superior virus-specific CD8+ T-cell responses in infected people. We aimed here to learn from comparing HIV-1 and HIV-2 mediated naive T cell priming in order to inform on ways to generate efficacious CD8+ T cells against HIV. To this end, we developed an unbiased in vitro system to compare the de novo induction of antigen-specific CD8+ T cell responses upon exposure to HIV-1 or HIV-2. We found that HIV-2 primed CD8+ T cells with enhanced effector potential and survival, in a type I interferon dependent manner. Accordingly, the use of the stimulator of interferon genes (STING) agonist cGAMP was able to mimic HIV-2 signaling for optimal T cell priming, and enabled the induction of CD8+ T cells with high polyfunctionality and antigen sensitivity directly from HIV-1 infected patient PBMCs. Harnessing the cGAS-STING pathway represents therefore a promising therapeutic approach to bolster antiviral CD8+ T cells in HIV-1 cure strategies.