Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Metabolic plasticity of HIV-specific CD8+ T cells is associated with enhanced antiviral potential and natural control of HIV-1 infection


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Different gene expression profiles in HIV-specific CD8+ TCMs from HICs and cART individuals.
Fig. 2: Differentially expressed genes linked to CD8+ T cell effector functions in HIV-specific CD8+ TCMs from HICs (red) and cART individuals (blue).
Fig. 3: Genes differentially expressed by HIV-specific CD8+ TCMs from HICs (red) and cART individuals (blue).
Fig. 4: Opposing profiles in HIV-specific CD8+ TCMs from HICs and cART individuals.
Fig. 5: Similarities in gene expression profiles in HIV-specific CD8+ T cells from HIV controllers with strong and weak responses.
Fig. 6: Different metabolite uptake by CD8+ TCMs from HICs and non-controllers.
Fig. 7: Metabolic plasticity versus glucose dependency of HIV-specific CD8+ T cells from HICs and cART individuals.
Fig. 8: Enhahncement by IL-15 of the antiviral capacity of HIV-specific CD8+ T cells from cART individuals.

Data availability

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.


  1. 1.

    Walker, B. & McMichael, A. The T-cell response to HIV. Cold Spring Harbor Perspect. Med. 2, a007054 (2012).

    Article  Google Scholar 

  2. 2.

    Appay, V. et al. Dynamics of T cell responses in HIV Infection. J. Immunol. 168, 3660–3666 (2002).

    CAS  Article  Google Scholar 

  3. 3.

    Takata, H. et al. Delayed differentiation of potent effector CD8+ T cells reducing viremia and reservoir seeding in acute HIV infection. Sci. Transl. Med. 9, eaag1809 (2017).

    Article  Google Scholar 

  4. 4.

    Migueles, S. A. et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat. Immunol. 3, 1061–1068 (2002).

    CAS  Article  Google Scholar 

  5. 5.

    Betts, M. R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).

    CAS  Article  Google Scholar 

  6. 6.

    Migueles, S. A. et al. Lytic granule loading of CD8+ T cells is required for HIV-infected cell elimination associated with immune control. Immunity 29, 1009–1021 (2008).

    CAS  Article  Google Scholar 

  7. 7.

    Saez-Cirion, A. & Pancino, G. HIV controllers: a genetically determined or inducible phenotype? Immunol. Rev. 254, 281–294 (2013).

    Article  Google Scholar 

  8. 8.

    Saez-Cirion, A. et al. HIV controllers exhibit potent CD8 T cell capacity to suppress HIV infection ex vivo and peculiar cytotoxic T lymphocyte activation phenotype. Proc. Natl Acad. Sci. USA 104, 6776–6781 (2007).

    CAS  Article  Google Scholar 

  9. 9.

    Angin, M. et al. Preservation of lymphopoietic potential and virus suppressive capacity by CD8+ T cells in HIV-2-infected controllers. J. Immunol. 197, 2787–2795 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Lecuroux, C. et al. CD8 T-cells from most HIV-infected patients lack ex vivo HIV-suppressive capacity during acute and early infection. PLoS ONE 8, e59767 (2013).

    CAS  Article  Google Scholar 

  11. 11.

    Tansiri, Y., Rowland-Jones, S. L., Ananworanich, J. & Hansasuta, P. Clinical outcome of HIV viraemic controllers and noncontrollers with normal CD4 counts is exclusively determined by antigen-specific CD8+ T-cell-mediated HIV suppression. PLoS ONE 10, e0118871 (2015).

    Article  Google Scholar 

  12. 12.

    Buckheit, R. W. 3rd, Salgado, M., Silciano, R. F. & Blankson, J. N. Inhibitory potential of subpopulations of CD8+ T cells in HIV-1-infected elite suppressors. J. Virol. 86, 13679–13688 (2012).

    CAS  Article  Google Scholar 

  13. 13.

    Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

    CAS  Article  Google Scholar 

  14. 14.

    Burgers, W. A. et al. Association of HIV-specific and total CD8+ T memory phenotypes in subtype C HIV-1 infection with viral set point. J. Immunol. 182, 4751–4761 (2009).

    CAS  Article  Google Scholar 

  15. 15.

    Ladell, K. et al. Central memory CD8+ T cells appear to have a shorter lifespan and reduced abundance as a function of HIV disease progression. J. Immunol. 180, 7907–7918 (2008).

    CAS  Article  Google Scholar 

  16. 16.

    Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

    CAS  Article  Google Scholar 

  17. 17.

    Flatz, L. et al. Single-cell gene-expression profiling reveals qualitatively distinct CD8 T cells elicited by different gene-based vaccines. Proc. Natl Acad. Sci. USA 108, 5724–5729 (2011).

    CAS  Article  Google Scholar 

  18. 18.

    Saez-Cirion, A. et al. Heterogeneity in HIV suppression by CD8 T cells from HIV controllers: association with Gag-specific CD8 T cell responses. J. Immunol. 182, 7828–7837 (2009).

    CAS  Article  Google Scholar 

  19. 19.

    Cocchi, F. et al. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270, 1811–1815 (1995).

    CAS  Article  Google Scholar 

  20. 20.

    Phan, A. T. & Goldrath, A. W. Hypoxia-inducible factors regulate T cell metabolism and function. Mol. Immunol. 68, 527–535 (2015).

    CAS  Article  Google Scholar 

  21. 21.

    Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).

    CAS  Article  Google Scholar 

  22. 22.

    Pollizzi, K. N. et al. mTORC1 and mTORC2 selectively regulate CD8+ T cell differentiation. J. Clin. Invest. 125, 2090–2108 (2015).

    Article  Google Scholar 

  23. 23.

    Hung, C. M., Garcia-Haro, L., Sparks, C. A. & Guertin, D. A. mTOR-dependent cell survival mechanisms. Cold Spring Harb Perspect. Biol. 4, a008771 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    CAS  Article  Google Scholar 

  25. 25.

    Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).

    CAS  Article  Google Scholar 

  26. 26.

    Ruschke, K. et al. Repin1 maybe involved in the regulation of cell size and glucose transport in adipocytes. Biochem. Biophys. Res. Commun. 400, 246–251 (2010).

    CAS  Article  Google Scholar 

  27. 27.

    Lecuroux, C. et al. Both HLA-B*57 and plasma HIV RNA levels contribute to the HIV-specific CD8+ T cell response in HIV controllers. J. Virol. 88, 176–187 (2014).

    Article  Google Scholar 

  28. 28.

    Ndhlovu, Z. M. et al. Elite controllers with low to absent effector CD8+ T cell responses maintain highly functional, broadly directed central memory responses. J. Virol. 86, 6959–6969 (2012).

    CAS  Article  Google Scholar 

  29. 29.

    van der Windt, G. J. & Pearce, E. L. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol. Rev. 249, 27–42 (2012).

    Article  Google Scholar 

  30. 30.

    Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J. Clin. Invest. 124, 4004–4016 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Schurich, A. et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 16, 1243–1252 (2016).

    CAS  Article  Google Scholar 

  32. 32.

    Gerasimenko, J. V. et al. Menadione-induced apoptosis: roles of cytosolic Ca2+ elevations and the mitochondrial permeability transition pore. J. Cell Sci. 115, 485–497 (2002).

    CAS  PubMed  Google Scholar 

  33. 33.

    Freeman, G. J., Wherry, E. J., Ahmed, R. & Sharpe, A. H. Reinvigorating exhausted HIV-specific T cells via PD-1-PD-1 ligand blockade. J. Exp. Med. 203, 2223–2227 (2006).

    CAS  Article  Google Scholar 

  34. 34.

    Valle-Casuso, J. C. et al. Cellular metabolism is a major determinant of HIV-1 reservoir seeding in CD4+ T cells and offers an opportunity to tackle infection. Cell Metab. 29, 611–626 e615 (2019).

    CAS  Article  Google Scholar 

  35. 35.

    Planas, D. et al. HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms. JCI Insight 2, 93230 (2017).

    Article  Google Scholar 

  36. 36.

    Donnelly, R. P. et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J. Immunol. 193, 4477–4484 (2014).

    CAS  Article  Google Scholar 

  37. 37.

    Petrovas, C. et al. HIV-specific CD8+ T cells exhibit markedly reduced levels of Bcl-2 and Bcl-xL. J. Immunol. 172, 4444–4453 (2004).

    CAS  Article  Google Scholar 

  38. 38.

    Shasha, D. et al. Elite controller CD8+ T cells exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors. J. Leukoc. Biol. 100, 1425–1433 (2016).

    CAS  Article  Google Scholar 

  39. 39.

    Gautam, S. et al. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat. Immunol. 20, 337–349 (2019).

    CAS  Article  Google Scholar 

  40. 40.

    Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 1130–1144 (2012).

    CAS  Article  Google Scholar 

  41. 41.

    Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    CAS  Article  Google Scholar 

  42. 42.

    Noel, N. et al. Long-term spontaneous control of HIV-1 is related to low frequency of infected cells and inefficient viral reactivation. J. Virol. 90, 6148–6158 (2016).

    CAS  Article  Google Scholar 

  43. 43.

    Petrovas, C. et al. Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells. Blood 109, 2505–2513 (2007).

    CAS  Article  Google Scholar 

  44. 44.

    Perrin, S. et al. HIV-1 infection and first line ART induced differential responses in mitochondria from blood lymphocytes and monocytes: the ANRS EP45 ‘Aging’ study. PLoS ONE 7, e41129 (2012).

    CAS  Article  Google Scholar 

  45. 45.

    Raud, B., McGuire, P. J., Jones, R. G., Sparwasser, T. & Berod, L. Fatty acid metabolism in CD8+ T cell memory: challenging current concepts. Immunol. Rev. 283, 213–231 (2018).

    CAS  Article  Google Scholar 

  46. 46.

    Phan, A. T. et al. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 45, 1024–1037 (2016).

    CAS  Article  Google Scholar 

  47. 47.

    Quintana, A. et al. T cell activation requires mitochondrial translocation to the immunological synapse. Proc. Natl Acad. Sci. USA 104, 14418–14423 (2007).

    CAS  Article  Google Scholar 

  48. 48.

    Cannarile, M. A. et al. Transcriptional regulator Id2 mediates CD8+ T cell immunity. Nat. Immunol. 7, 1317–1325 (2006).

    CAS  Article  Google Scholar 

  49. 49.

    Zhang, Z., Rahme, G. J., Chatterjee, P. D., Havrda, M. C. & Israel, M. A. ID2 promotes survival of glioblastoma cells during metabolic stress by regulating mitochondrial function. Cell Death Dis 8, e2615 (2017).

    CAS  Article  Google Scholar 

  50. 50.

    de Jong, A. J., Kloppenburg, M., Toes, R. E. & Ioan-Facsinay, A. Fatty acids, lipid mediators, and T-cell function. Front. Immunol. 5, 483 (2014).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Champagne, D. P. et al. Fine-tuning of CD8+ T cell mitochondrial metabolism by the respiratory chain repressor MCJ dictates protection to influenza virus. Immunity 44, 1299–1311 (2016).

    CAS  Article  Google Scholar 

  52. 52.

    Gardner, K., Hall, P. A., Chinnery, P. F. & Payne, B. A. HIV treatment and associated mitochondrial pathology: review of 25 years of in vitro, animal, and human studies. Toxicol. Pathol. 42, 811–822 (2014).

    Article  Google Scholar 

  53. 53.

    Margolis, A. M., Heverling, H., Pham, P. A. & Stolbach, A. A review of the toxicity of HIV medications. J. Med. Toxicol. 10, 26–39 (2014).

    CAS  Article  Google Scholar 

  54. 54.

    Siska, P. J. & Rathmell, J. C. T cell metabolic fitness in antitumor immunity. Trends Immunol. 36, 257–264 (2015).

    CAS  Article  Google Scholar 

  55. 55.

    Sathekge, M., Maes, A., Kgomo, M. & Van de Wiele, C. Fluorodeoxyglucose uptake by lymph nodes of HIV patients is inversely related to CD4 cell count. Nucl. Med. Commun. 31, 137–140 (2010).

    Article  Google Scholar 

  56. 56.

    Fischer, K. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109, 3812–3819 (2007).

    CAS  Article  Google Scholar 

  57. 57.

    Fisicaro, P. et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat. Med. 23, 327–336 (2017).

    CAS  Article  Google Scholar 

  58. 58.

    Mueller, Y. M. et al. IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 101, 1024–1029 (2003).

    CAS  Article  Google Scholar 

  59. 59.

    Watson, D. C. et al. Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes. PLoS Pathog. 14, e1006902 (2018).

    Article  Google Scholar 

  60. 60.

    Chang, C. H. & Pearce, E. L. Emerging concepts of T cell metabolism as a target of immunotherapy. Nat. Immunol. 17, 364–368 (2016).

    CAS  Article  Google Scholar 

  61. 61.

    Saez-Cirion, A., Shin, S. Y., Versmisse, P., Barre-Sinoussi, F. & Pancino, G. Ex vivo T cell-based HIV suppression assay to evaluate HIV-specific CD8+ T-cell responses. Nat. Protoc. 5, 1033–1041 (2010).

    CAS  Article  Google Scholar 

  62. 62.

    O’Doherty, U., Swiggard, W. J. & Malim, M. H. Human immunodeficiency virus type 1 spinoculation enhances infection through virus binding. J. Virol. 74, 10074–10080 (2000).

    Article  Google Scholar 

  63. 63.

    Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).

    Article  Google Scholar 

  64. 64.

    Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. Ser. B (Methodol.) 57, 189–300 (1995).

    Google Scholar 

  65. 65.

    van der Maaten, L. & Hinton, G. Visualizing data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008).

    Google Scholar 

  66. 66.

    Hofmann-Lehmann, R. et al. Sensitive and robust one-tube real-time reverse transcriptase-polymerase chain reaction to quantify SIV RNA load: comparison of one- versus two-enzyme systems. AIDS Res. Hum. Retroviruses 16, 1247–1257 (2000).

    CAS  Article  Google Scholar 

  67. 67.

    Bruel, T. et al. Long-term control of simian immunodeficiency virus (SIV) in cynomolgus macaques not associated with efficient SIV-specific CD8+ T-cell responses. J. Virol. 89, 3542–3556 (2015).

    CAS  Article  Google Scholar 

Download references


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.

Author information




M.A., C.P., C.L., V.M. and J.C.V.-C. performed the experiments. M.A., S.V., M.-A.D. and A.S-C. analysed the data. L.W., C.G., L.M., F.B. and O.L. contributed to the inclusion of study participants, obtaining clinical information and its validation. C.P., B.V., R.L.G. and A.S.-C. contributed to the design and development of the macaque study. G.P., M.M.-T., O.L. and A.S.-C. contributed to the conception of the study. M.A., O.L. and A.S.-C. designed the study. M.A. and A.S.-C. drafted the article. All the authors critically reviewed the manuscript.

Corresponding author

Correspondence to Asier Sáez-Cirión.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information: Primary Handling Editor: Ana Mateus

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–17 and Supplementary Tables 1–6

Reporting Summary

Supplementary Data Set 1

Gene expression values of HIV-specific CD8+ TCMs

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing