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

Abstract

Virus-specific CD8+ 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 stemness properties, high survival, polyfunctionality, proliferative capacity, metabolic plasticity, and antiviral potential. The development and maintenance of such qualities by memory CD8+ 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+ T cells from noncontrollers promoted functional capacities associated with natural control of infection. Features of such reprogrammed cells included enrichment in TCF-1+ less-differentiated subsets, a superior response to antigen, enhanced survival, polyfunctionality, metabolic plasticity, less mTORC1 dependency, an improved response to γ-chain cytokines, and a stronger HIV-suppressive capacity. Thus, such CD8+ 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.

• Authors: Federico Perdomo-Celis, Caroline Passaes, Valérie Monceaux, Stevenn Volant, Faroudy Boufassa, Pierre de Truchis, Morgane Marcou, Katia Bourdic, Laurence Weiss, Corinne Jung, Christine Bourgeois, Cécile Goujard, Laurence Meyer, Michaela Müller-Trutwin, Olivier Lambotte, Asier Sáez-Cirión
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 132 Issue 11 (06 01 2022) ISSN: 1558-8238 [Electronic] United States
• PMID: 35380989 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)

Chemical References

• Glycogen Synthase Kinase 3

Topics

• CD8-Positive T-Lymphocytes
• Glycogen Synthase Kinase 3 (metabolism)
• HIV Infections
• HIV-1
• Humans
• Viremia