Reprogramming dysfunctional [CD8.sup.+] T cells to promote properties associated with natural HIV control

Virus-specific [CD8.sup.+] T cells play a central role in HIV-1 natural controllers to maintain suppressed viremia in the absence of antiretroviral therapy. These cells display a memory program that confers them sternness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory [CD8.sup.+] T cells appear crucial to achieving natural HIV-1 control. Here, we show that targeting the signaling pathways Wnt/transcription factor T cell factor 1 (Wnt/TCF-1) and mTORC through GSK3 inhibition to reprogram HIV-specific [CD8.sup.+] T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in [TCF-1.sup.+] less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to [gamma]-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such [CD8.sup.+] T cell reprogramming, combined with other available immunomodulators, might represent a promising strategy for adoptive cell therapy in the search for an HIV-1 cure.
Introduction For activation and differentiation, [CD8.sup.+] T cells require T cell receptor (TCR) signals provided by peptide/MHC class I, together with costimulation, and cytokines. The amount and duration of these [...]