Spontaneous control of human immunodeficiency virus (HIV) is generally associated with an enhanced capacity of CD8+ T cells to eliminate infected CD4+ T cells, but the molecular characteristics of these highly functional CD8+ T cells are largely unknown. In the present study, using single-cell analysis, it was shown that HIV-specific, central memory CD8+ T cells from spontaneous HIV controllers (HICs) and antiretrovirally treated non-controllers have opposing transcriptomic profiles. Genes linked to effector functions and survival are upregulated in cells from HICs. In contrast, genes associated with activation, exhaustion and glycolysis are upregulated in cells from non-controllers. It was shown that HIV-specific CD8+ T cells from non-controllers are largely glucose dependent, whereas those from HICs have more diverse metabolic resources that enhance both their survival potential and their capacity to develop anti-HIV effector functions. The functional efficiency of the HIV-specific CD8+ T cell response in HICs is thus engraved in their memory population and related to their metabolic programme. Metabolic reprogramming in vitro through interleukin-15 treatment abrogated the glucose dependency and enhanced the antiviral potency of HIV-specific CD8+ T cells from non-controllers.
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All data generated or analysed during the present study are available from the corresponding author upon request. Gene expression data are included in this article and its supplementary information files.
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The authors wish to thank A. Tadesse, S. Hendou, A. Essat, C. Jung and K. Bourdic for help with the inclusion of HIV-infected individuals. They also wish to thank D. Desjardin and N. Bosquet for help with the macaque studies, and especially the investigators, clinical personal and HIV-infected individuals participating in the ANRS CO6 PRIMO and ANRS CO21 cohorts for their cooperation. The authors thank the Cytometry and Biomarkers UTechS platform at Institut Pasteur and the personnel from the Infectious Disease Models and Innovative Therapies (IDMIT) platform for technical support. D. Young, a medical English editor, supported with funds from the AS-C laboratory, provided English editorial assistance during the preparation of this manuscript. The present study was conducted with funds from the French National Agency for Research on AIDS and Viral Hepatitis (ANRS), MSDAVENIR and the European Union (EU)’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 706871. M.A. received support from the EU (grant no. 706871) and complementary support from Sidaction. C.P. received support from the ANRS. J.C.V.-C. received support from Institut Pasteur through the Roux-Cantarini programme. The ANRS CO6 and CO21 cohorts were sponsored and funded by the ANRS. IDMIT infrastructure was supported by the French government Programme d’Investissements d’Avenir under grant no. ANR-11-INBS-0008.
The authors declare no competing interests.
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Angin, M., Volant, S., Passaes, C. et al. Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection. Nat Metab 1, 704–716 (2019) doi:10.1038/s42255-019-0081-4
Nature Metabolism (2019)