Skip to main content

Thank you for visiting nature.com. 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.

Immunometabolism and HIV-1 pathogenesis: food for thought

Abstract

Antiretroviral therapies efficiently block HIV-1 replication but need to be maintained for life. Moreover, chronic inflammation is a hallmark of HIV-1 infection that persists despite treatment. There is, therefore, an urgent need to better understand the mechanisms driving HIV-1 pathogenesis and to identify new targets for therapeutic intervention. In the past few years, the decisive role of cellular metabolism in the fate and activity of immune cells has been uncovered, as well as its impact on the outcome of infectious diseases. Emerging evidence suggests that immunometabolism has a key role in HIV-1 pathogenesis. The metabolic pathways of CD4+ T cells and macrophages determine their susceptibility to infection, the persistence of infected cells and the establishment of latency. Immunometabolism also shapes immune responses against HIV-1, and cell metabolic products are key drivers of inflammation during infection. In this Review, we summarize current knowledge of the links between HIV-1 infection and immunometabolism, and we discuss the potential opportunities and challenges for therapeutic interventions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The association between metabolic status and HIV-1 susceptibility of CD4+ T cells.
Fig. 2: Metabolic pathways that affect HIV-1 replication.
Fig. 3: Schematic illustration of the different metabolic profiles of memory CD8+ T cells associated with control or progression of HIV-1 infection.
Fig. 4: Potential therapeutic interventions targeting immunometabolism in the context of HIV-1 infection.

References

  1. Beisel, W. R. Metabolic response to infection. Annu. Rev. Med. 26, 9–20 (1975).

    CAS  PubMed  Google Scholar 

  2. Oren, R., Farnham, A. E., Saito, K., Milofsky, E. & Karnovsky, M. L. Metabolic patterns in three types of phagocytizing cells. J. Cell Biol. 17, 487–501 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

    PubMed  PubMed Central  Google Scholar 

  5. 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).

    PubMed  PubMed Central  Google Scholar 

  6. Waickman, A. T. & Powell, J. D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009). This study finds that the mTOR pathway is a major regulator of CD8+ T cell responses. The mTOR inhibitor rapamycin improves the generation of memory responses after acute lymphocytic choriomeningitis virus infection in mice and after vaccination in mice and non-human primate models.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Goodwin, C. M., Xu, S. & Munger, J. Stealing the keys to the kitchen: viral manipulation of the host cell metabolic network. Trends Microbiol. 23, 789–798 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Pallett, L. J., Schmidt, N. & Schurich, A. T cell metabolism in chronic viral infection. Clin. Exp. Immunol. 197, 143–152 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sanchez, E. L. & Lagunoff, M. Viral activation of cellular metabolism. Virology 479-480, 609–618 (2015).

    CAS  PubMed  Google Scholar 

  12. Manel, N. et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell 115, 449–459 (2003).

    CAS  PubMed  Google Scholar 

  13. Takeuchi, Y. et al. Feline leukemia virus subgroup B uses the same cell surface receptor as gibbon ape leukemia virus. J. Virol. 66, 1219–1222 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. von Laer, D. et al. Entry of amphotropic and 10A1 pseudotyped murine retroviruses is restricted in hematopoietic stem cell lines. J. Virol. 72, 1424–1430 (1998).

    Google Scholar 

  15. Marin, M., Lavillette, D., Kelly, S. M. & Kabat, D. N-linked glycosylation and sequence changes in a critical negative control region of the ASCT1 and ASCT2 neutral amino acid transporters determine their retroviral receptor functions. J. Virol. 77, 2936–2945 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Appay, V. & Sauce, D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J. Pathol. 214, 231–241 (2008).

    CAS  PubMed  Google Scholar 

  17. Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).

    CAS  PubMed  Google Scholar 

  18. Hsu, D. C. & Sereti, I. Serious non-AIDS events: therapeutic targets of immune activation and chronic inflammation in HIV infection. Drugs 76, 533–549 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Stevenson, M., Stanwick, T. L., Dempsey, M. P. & Lamonica, C. A. HIV-1 replication is controlled at the level of T cell activation and proviral integration. EMBO J. 9, 1551–1560 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pan, X., Baldauf, H. M., Keppler, O. T. & Fackler, O. T. Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. Cell Res. 23, 876–885 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Buzon, M. J. et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat. Med. 20, 139–142 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Schnittman, S. M. et al. Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals. Proc. Natl Acad. Sci. USA 87, 6058–6062 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).

    CAS  PubMed  Google Scholar 

  24. Patsoukis, N. et al. The role of metabolic reprogramming in T cell fate and function. Curr. Trends Immunol. 17, 1–12 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Geltink, R. I. K., Kyle, R. L. & Pearce, E. L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 36, 461–488 (2018).

    CAS  PubMed  Google Scholar 

  26. Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009). This study finds that mitochondria, and in particular FAO, are important for the establishment of memory CD8+ T cell responses, and further finds that energy metabolism could be pharmacologically altered to induce CD8+ T cell memory.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gao, D., Rahbar, R. & Fish, E. N. CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells. Open Biol. 6, 160122 (2016).

    PubMed  PubMed Central  Google Scholar 

  28. Zheng, Y. et al. Structure of CC chemokine receptor 5 with a potent chemokine antagonist reveals mechanisms of chemokine recognition and molecular mimicry by HIV. Immunity 46, 1005–1017.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Clerc, I. et al. Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells. Nat. Metab. 1, 717–730 (2019). This study evaluates the crucial roles of glutaminolysis, mitochondrial biomass and OXPHOS in HIV-1 infection of CD4+ T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kavanagh Williamson, M. et al. Upregulation of glucose uptake and hexokinase activity of primary human CD4+ T cells in response to infection with HIV-1. Viruses 10, 114 (2018).

    PubMed Central  Google Scholar 

  31. Loisel-Meyer, S. et al. Glut1-mediated glucose transport regulates HIV infection. Proc. Natl Acad. Sci. USA 109, 2549–2554 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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). This study shows that HIV-1 selectively infects CD4+ T cells with high levels of OXPHOS and glycolysis, independent of their activation and/or differentiation phenotype. Inhibition of glycolysis can impact infection, viability of infected cells and level of inducible virus from primary cells of individuals positive for HIV-1, which suggests that glycolysis may be a target for metabolic interventions against the HIV-1 reservoir.

    CAS  PubMed  Google Scholar 

  33. Hegedus, A., Kavanagh Williamson, M. & Huthoff, H. HIV-1 pathogenicity and virion production are dependent on the metabolic phenotype of activated CD4+ T cells. Retrovirology 11, 98 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Hegedus, A. et al. Evidence for altered glutamine metabolism in human immunodeficiency virus type 1 infected primary human CD4+ T cells. AIDS Res. Hum. Retroviruses 33, 1236–1247 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hollenbaugh, J. A., Munger, J. & Kim, B. Metabolite profiles of human immunodeficiency virus infected CD4+ T cells and macrophages using LC-MS/MS analysis. Virology 415, 153–159 (2011).

    CAS  PubMed  Google Scholar 

  36. Ganor, Y. et al. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat. Microbiol. 4, 633–644 (2019).

    CAS  PubMed  Google Scholar 

  37. Kruize, Z. & Kootstra, N. A. The role of macrophages in HIV-1 persistence and pathogenesis. Front. Microbiol. 10, 2828 (2019).

    PubMed  PubMed Central  Google Scholar 

  38. Russell, D. G., Huang, L. & VanderVen, B. C. Immunometabolism at the interface between macrophages and pathogens. Nat. Rev. Immunol 19, 291–304 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).

    CAS  PubMed  Google Scholar 

  40. Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    CAS  PubMed  Google Scholar 

  42. Cassol, E., Cassetta, L., Alfano, M. & Poli, G. Macrophage polarization and HIV-1 infection. J. Leukoc. Biol. 87, 599–608 (2010).

    CAS  PubMed  Google Scholar 

  43. Cassol, E., Cassetta, L., Rizzi, C., Alfano, M. & Poli, G. M1 and M2a polarization of human monocyte-derived macrophages inhibits HIV-1 replication by distinct mechanisms. J. Immunol. 182, 6237–6246 (2009).

    CAS  PubMed  Google Scholar 

  44. Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).

    CAS  PubMed  Google Scholar 

  45. Castellano, P., Prevedel, L., Valdebenito, S. & Eugenin, E. A. HIV infection and latency induce a unique metabolic signature in human macrophages. Sci. Rep. 9, 1–14 (2019).

    CAS  Google Scholar 

  46. Datta, P. K. et al. Glutamate metabolism in HIV-1 infected macrophages: role of HIV-1 Vpr. Cell Cycle. 15, 2288–2298 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sen, S. et al. Role of hexokinase-1 in the survival of HIV-1-infected macrophages. Cell Cycle. 14, 980–989 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ray, J. P. et al. The interleukin-2–mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690–702 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Perreau, M. et al. Follicular helper T cells serve as the major CD4 T cell compartment for HIV-1 infection, replication, and production. J. Exp. Med. 210, 143–156 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mikhailova, A. et al. Anti-apoptotic clone 11 derived peptides induce in vitro death of CD4+ T cells susceptible to HIV-1 infection. J Virol. 94, e00611-20 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Pacella, I. et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth. Proc. Natl Acad. Sci. USA 115, E6546–E6555 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Kuo, H. H. et al. Anti-apoptotic protein BIRC5 maintains survival of HIV-1-infected CD4+ T cells. Immunity 48, 1183–1194.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466–2485 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Amie, S. M., Noble, E. & Kim, B. Intracellular nucleotide levels and the control of retroviral infections. Virology 436, 247–254 (2013).

    CAS  PubMed  Google Scholar 

  55. Diamond, T. L. et al. Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. J. Biol. Chem. 279, 51545–51553 (2004).

    CAS  PubMed  Google Scholar 

  56. Allouch, A. et al. p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway. Proc. Natl Acad. Sci. USA 110, E3997–E4006 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Valle-Casuso, J. C. et al. p21 restricts HIV-1 in monocyte-derived dendritic cells through the reduction of deoxynucleoside triphosphate biosynthesis and regulation of SAMHD1 antiviral activity. J. Virol. 91, e01324-17 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. Mathews, C. K. Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat. Rev. Cancer 15, 528–539 (2015).

    CAS  PubMed  Google Scholar 

  59. Descours, B. et al. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology 9, 87 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lahouassa, H. et al. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13, 223–228 (2012). This paper shows that SAMHD1 restricts HIV-1 infection by hydrolysing intracellular dNTPs and lowering their concentrations below those required for viral DNA synthesis by reverse transcriptase, an action that can be alleviated by the addition of exogenous deoxynucleosides.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Goldstone, D. C. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382 (2011).

    CAS  PubMed  Google Scholar 

  62. Bergamaschi, A. et al. The CDK inhibitor p21Cip1/WAF1 is induced by FcγR activation and restricts the replication of human immunodeficiency virus type 1 and related primate lentiviruses in human macrophages. J. Virol. 83, 12253–12265 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen, H. et al. CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21. J. Clin. Invest. 121, 1549–1560 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bantug, G. R., Galluzzi, L., Kroemer, G. & Hess, C. The spectrum of T cell metabolism in health and disease. Nat. Rev. Immunol. 18, 19–34 (2018).

    CAS  PubMed  Google Scholar 

  65. Coomer, C. A. et al. Single-cell glycolytic activity regulates membrane tension and HIV-1 fusion. PLoS Pathog. 16, e1008359 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Duran, R. V. et al. Glutaminolysis activates Rag–mTORC1 signaling. Mol. Cell 47, 349–358 (2012).

    CAS  PubMed  Google Scholar 

  67. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Angin, M. 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). This paper shows that memory CD8+ T cells from HIV-1 elite controllers have broad antiviral and survival gene expression in single-cell analysis, in contrast to T cells from non-controllers, which express high levels of HIF1α and mTOR, and are dependent on glycolysis, but can be metabolically reprogrammed after IL-15 treatment towards OXPHOS with improved antiviral function.

    CAS  PubMed  Google Scholar 

  69. Planas, D. et al. HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms. JCI Insight 2, e93230 (2017). This paper finds that the PI3K–AKT–mTORC1 pathway is instrumental in the increased susceptibility of CCR6+CD4+ T cells induced by retinoic acid to HIV-1, which could in turn be blocked by mTOR inhibitors.

    PubMed Central  Google Scholar 

  70. Heredia, A. et al. Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice. Proc. Natl Acad. Sci. USA 112, 9412–9417 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Heredia, A. et al. Rapamycin causes down-regulation of CCR5 and accumulation of anti-HIV β-chemokines: an approach to suppress R5 strains of HIV-1. Proc. Natl Acad. Sci. USA 100, 10411–10416 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Besnard, E. et al. The mTOR complex controls HIV latency. Cell Host Microbe 20, 785–797 (2016). This study finds that the mTOR complex is a regulator of HIV-1 latency and that inhibition of mTOR prevents HIV-1 reactivation from latency.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Zhou, Q., Chen, D., Pierstorff, E. & Luo, K. Transcription elongation factor P-TEFb mediates Tat activation of HIV-1 transcription at multiple stages. EMBO J. 17, 3681–3691 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. van Montfort, T. et al. Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K–Akt–mTOR pathway. EBioMedicine 42, 97–108 (2019).

    PubMed  PubMed Central  Google Scholar 

  75. Lochner, M., Berod, L. & Sparwasser, T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 36, 81–91 (2015).

    CAS  PubMed  Google Scholar 

  76. Harlan, W. R. Jr & Wakil, S. J. Synthesis of fatty acids in animal tissues. I. Incorporation of C14-acetyl coenzyme a into a variety of long chain fatty acids by subcellular particles. J. Biol. Chem. 238, 3216–3223 (1963).

    CAS  PubMed  Google Scholar 

  77. Bryant, M. & Ratner, L. Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc. Natl Acad. Sci. USA 87, 523–527 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Gottlinger, H. G., Sodroski, J. G. & Haseltine, W. A. Role of capsid precursor processing and myristoylation in morphogenesis and infectivity of human immunodeficiency virus type 1. Proc. Natl Acad. Sci. USA 86, 5781–5785 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lindwasser, O. W. & Resh, M. D. Myristoylation as a target for inhibiting HIV assembly: unsaturated fatty acids block viral budding. Proc. Natl Acad. Sci. USA 99, 13037–13042 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Bukrinsky, M. & Sviridov, D. Human immunodeficiency virus infection and macrophage cholesterol metabolism. J. Leukoc. Biol. 80, 1044–1051 (2006).

    CAS  PubMed  Google Scholar 

  81. Aloia, R. C., Tian, H. & Jensen, F. C. Lipid composition and fluidity of the human immunodeficiency virus envelope and host cell plasma membranes. Proc. Natl Acad. Sci. USA 90, 5181–5185 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).

    CAS  PubMed  Google Scholar 

  83. Van Lint, C., Emiliani, S., Ott, M. & Verdin, E. Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation. EMBO J. 15, 1112–1120 (1996).

    PubMed  PubMed Central  Google Scholar 

  84. Jiang, G. et al. HIV latency is reversed by ACSS2-driven histone crotonylation. J. Clin. Invest. 128, 1190–1198 (2018).

    PubMed  PubMed Central  Google Scholar 

  85. Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell. 58, 203–215 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Hazleton, J. E., Berman, J. W. & Eugenin, E. A. Purinergic receptors are required for HIV-1 infection of primary human macrophages. J. Immunol. 188, 4488–4495 (2012).

    CAS  PubMed  Google Scholar 

  87. Paoletti, A. et al. HIV-1 envelope overcomes NLRP3-mediated inhibition of F-actin polymerization for viral entry. Cell Rep. 28, 3381–3394.e7 (2019).

    CAS  PubMed  Google Scholar 

  88. Seror, C. et al. Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J. Exp. Med. 208, 1823–1834 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Matheson, N. J. et al. Cell surface proteomic map of HIV infection reveals antagonism of amino acid metabolism by Vpu and Nef. Cell Host Microbe 18, 409–423 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Barrero, C. A. et al. HIV-1 Vpr modulates macrophage metabolic pathways: a SILAC-based quantitative analysis. PLoS ONE 8, e68376 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Rasheed, S., Yan, J. S., Lau, A. & Chan, A. S. HIV replication enhances production of free fatty acids, low density lipoproteins and many key proteins involved in lipid metabolism: a proteomics study. PLoS ONE 3, e3003 (2008).

    PubMed  PubMed Central  Google Scholar 

  92. Zheng, Y. H., Plemenitas, A., Fielding, C. J. & Peterlin, B. M. Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions. Proc. Natl Acad. Sci. USA 100, 8460–8465 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009). This paper presents a comprehensive overview of chronic viral infections and how the immune system reacts to them.

    CAS  PubMed  Google Scholar 

  95. Koup, R. A. et al. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J. Virol. 68, 4650–4655 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Ndhlovu, Z. M. et al. Magnitude and kinetics of CD8+ T cell activation during hyperacute HIV infection impact viral set point. Immunity 43, 591–604 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  98. Saez-Cirion, A. & Manel, N. Immune responses to retroviruses. Annu. Rev. Immunol. 36, 193–220 (2018).

    CAS  PubMed  Google Scholar 

  99. 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  PubMed  PubMed Central  Google Scholar 

  100. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 25, 9543–9553 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45, 358–373 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Staron, M. M. et al. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 41, 802–814 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015). This paper shows that engagement of PD1 in primary human CD4+ T cells inhibits both glucose and amino acid transport and metabolism, and promotes fatty acid oxidation through CPT1A induction, in contrast to CTLA4 engagement, which inhibits glycolysis without enhancing FAO.

    CAS  PubMed  Google Scholar 

  104. McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    CAS  PubMed  Google Scholar 

  105. 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). This study shows how, within the same individuals, functional CMV-specific T cells have metabolic plasticity whereas HBV-specific T cells are characterized by glucose dependency, revealing metabolic differences in T cell responses against chronic and latent viral infections.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    CAS  PubMed  Google Scholar 

  107. Chatterjee, B. et al. CD8+ T cells retain protective functions despite sustained inhibitory receptor expression during Epstein–Barr virus infection in vivo. PLoS Pathog. 15, e1007748 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hertoghs, K. M. et al. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J. Clin. Invest. 120, 4077–4090 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Sauce, D. et al. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS 21, 2005–2013 (2007).

    CAS  PubMed  Google Scholar 

  110. Paiardini, M. et al. Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J. Immunol. 174, 2900–2909 (2005).

    CAS  PubMed  Google Scholar 

  111. 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).

    PubMed  PubMed Central  Google Scholar 

  112. Trautmann, L. et al. Profound metabolic, functional, and cytolytic differences characterize HIV-specific CD8 T cells in primary and chronic HIV infection. Blood 120, 3466–3477 (2012). This study shows that HIV-1-specific CD8+ T cells during primary infection are characterized by an altered metabolic programme that results from hyperproliferation and stress-induced signals generated during acute infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Huster, K. M. et al. Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets. Proc. Natl Acad. Sci. USA 101, 5610–5615 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Barili, V. et al. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat. Commun. 11, 604 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Radziewicz, H. et al. Impaired hepatitis C virus (HCV)-specific effector CD8+ T cells undergo massive apoptosis in the peripheral blood during acute HCV infection and in the liver during the chronic phase of infection. J. Virol. 82, 9808–9822 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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). This paper shows, by studying the transcriptome of individuals with acute or chronic HBV infection and those who resolve the infection spontaneously, a clear signal linking mitochondrial dysfunction to T cell exhaustion, suggesting that interventions that improve mitochondrial function may reverse T cell exhaustion.

    CAS  PubMed  Google Scholar 

  117. McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213–221 (2018).

    CAS  PubMed  Google Scholar 

  118. Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kallies, A., Zehn, D. & Utzschneider, D. T. Precursor exhausted T cells: key to successful immunotherapy? Nat. Rev. Immunol. 20, 128–136 (2020).

    CAS  PubMed  Google Scholar 

  120. Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840–855.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016). This study shows that expression of TCF1 is crucial for the establishment of memory-like responses against chronic viral infections.

    CAS  PubMed  Google Scholar 

  123. Boettler, T. et al. Expression of the interleukin-7 receptor α chain (CD127) on virus-specific CD8+ T cells identifies functionally and phenotypically defined memory T cells during acute resolving hepatitis B virus infection. J. Virol. 80, 3532–3540 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  125. Lecuroux, C. et al. Antiretroviral therapy initiation during primary HIV infection enhances both CD127 expression and the proliferative capacity of HIV-specific CD8+ T cells. AIDS. 23, 1649–1658 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 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  PubMed  Google Scholar 

  128. 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  PubMed  PubMed Central  Google Scholar 

  129. Rutishauser, R. L. et al. TCF-1 regulates the stem-like memory potential of HIV-specific CD8+ T cells in elite controllers. Preprint at bioRxiv https://doi.org/10.1101/2020.01.07.894535 (2020).

  130. 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  PubMed  PubMed Central  Google Scholar 

  131. Chowdhury, F. Z. et al. Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers. AIDS 32, 2669 (2018).

    CAS  PubMed  Google Scholar 

  132. Tarancon-Diez, L. et al. Immunometabolism is a key factor for the persistent spontaneous elite control of HIV-1 infection. EBioMedicine 42, 86–96 (2019).

    PubMed  PubMed Central  Google Scholar 

  133. Passaes, C. et al. Optimal maturation of the SIV-specific CD8+ T-cell response after primary infection is associated with natural control of SIV. ANRS SIC study. Preprint at bioRxiv https://doi.org/10.1101/2019.12.20.885459 (2019).

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

    CAS  PubMed  Google Scholar 

  135. Korencak, M. et al. Effect of HIV infection and antiretroviral therapy on immune cellular functions. JCI Insight 4, e126675 (2019). This study explores the impact of HIV-1 infection and antiretroviral treatment on the metabolic activities of different immune effectors.

    PubMed Central  Google Scholar 

  136. Arnoult, D., Petit, F., Lelievre, J. D. & Estaquier, J. Mitochondria in HIV-1-induced apoptosis. Biochem. Biophys. Res. Commun. 304, 561–574 (2003).

    CAS  PubMed  Google Scholar 

  137. Younes, S. A. et al. Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J. Clin. Invest. 128, 5083–5094 (2018).

    PubMed  PubMed Central  Google Scholar 

  138. O’Brien, K. L. & Finlay, D. K. Immunometabolism and natural killer cell responses. Nat. Rev. Immunol. 19, 282–290 (2019).

    PubMed  Google Scholar 

  139. Tsui, C. et al. Protein kinase C-β dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis. Immunity 48, 1144–1159.e5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Waters, L. R., Ahsan, F. M., Wolf, D. M., Shirihai, O. & Teitell, M. A. Initial B cell activation induces metabolic reprogramming and mitochondrial remodeling. iScience 5, 99–109 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Cubero, E. M. et al. IL-15 re-programming compensates for NK cell mitochondrial dysfunction in HIV-1 infection. Preprint at bioRxiv https://doi.org/10.1101/811117 (2019).

  142. Moir, S. & Fauci, A. S. B-cell responses to HIV infection. Immunol. Rev. 275, 33–48 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Deeks, S. G., Lewin, S. R. & Havlir, D. V. The end of AIDS: HIV infection as a chronic disease. Lancet 382, 1525–1533 (2013).

    PubMed  PubMed Central  Google Scholar 

  144. Kominsky, D. J., Campbell, E. L. & Colgan, S. P. Metabolic shifts in immunity and inflammation. J. Immunol. 184, 4062–4068 (2010).

    CAS  PubMed  Google Scholar 

  145. Butterfield, T. R. et al. Increased glucose transporter-1 expression on intermediate monocytes from HIV-infected women with subclinical cardiovascular disease. AIDS 31, 199–205 (2017).

    CAS  PubMed  Google Scholar 

  146. Palmer, C. S. et al. Increased glucose metabolic activity is associated with CD4+ T-cell activation and depletion during chronic HIV infection. AIDS 28, 297–309 (2014). This study shows that CD4+ T cells from individuals infected with HIV-1 are characterized by enhanced expression of GLUT1 that is not restored with antiretroviral treatment.

    CAS  PubMed  Google Scholar 

  147. Belkhir, L. et al. High FDG uptake on FDG-PET scan in HIV-1 infected patient with advanced disease. Acta Clin. Belg. 66, 419–421 (2011).

    CAS  PubMed  Google Scholar 

  148. Brust, D. et al. Fluorodeoxyglucose imaging in healthy subjects with HIV infection: impact of disease stage and therapy on pattern of nodal activation. AIDS 20, 495–503 (2006).

    PubMed  Google Scholar 

  149. Iyengar, S., Chin, B., Margolick, J. B., Sabundayo, B. P. & Schwartz, D. H. Anatomical loci of HIV-associated immune activation and association with viraemia. Lancet 362, 945–950 (2003).

    PubMed  Google Scholar 

  150. Tawakol, A. et al. Association of arterial and lymph node inflammation with distinct inflammatory pathways in human immunodeficiency virus infection. JAMA Cardiol. 2, 163–171 (2017). This paper shows that, in people with HIV-1 infection who are virologically suppressed, high glucose uptake in the aorta correlates with levels of inflammatory markers such as CRP and IL-6.

    PubMed  PubMed Central  Google Scholar 

  151. Sathekge, M., Maes, A. & Van de Wiele, C. FDG-PET imaging in HIV infection and tuberculosis. Semin. Nucl. Med. 43, 349–366 (2013).

    PubMed  Google Scholar 

  152. Hammoud, D. A. et al. Increased metabolic activity on 18F-fluorodeoxyglucose positron emission tomography–computed tomography in human immunodeficiency virus-associated immune reconstitution inflammatory syndrome. Clin. Infect. Dis. 68, 229–238 (2019).

    CAS  PubMed  Google Scholar 

  153. Henrich, T. J., Hsue, P. Y. & VanBrocklin, H. Seeing is believing: nuclear imaging of HIV persistence. Front. Immunol. 10, 2077 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: tryptophan’s metabolites in exercise, inflammation, mental health. Science 357, eaaf9794 (2017).

    PubMed  Google Scholar 

  155. Byakwaga, H. et al. The kynurenine pathway of tryptophan catabolism, CD4+ T-cell recovery, and mortality among HIV-infected Ugandans initiating antiretroviral therapy. J. Infect. Dis. 210, 383–391 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Favre, D. et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci. Transl Med. 2, 32ra36 (2010).

    PubMed  PubMed Central  Google Scholar 

  157. Vujkovic-Cvijin, I. et al. Dysbiosis of the gut microbiota is associated with HIV disease progression and tryptophan catabolism. Sci. Transl Med. 5, 193ra191 (2013). This study clearly links gut dysbiosis with systemic inflammation and with tryptophan metabolism in people with HIV-1 infection.

    Google Scholar 

  158. Dillon, S. M. et al. Low abundance of colonic butyrate-producing bacteria in HIV infection is associated with microbial translocation and immune activation. AIDS 31, 511–521 (2017).

    CAS  PubMed  Google Scholar 

  159. Guillen, Y. et al. Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection. Mucosal Immunol. 12, 232–246 (2019).

    CAS  PubMed  Google Scholar 

  160. Lee, S., Koh, J., Chang, Y., Kim, H. Y. & Chung, D. H. Invariant NKT cells functionally link microbiota-induced butyrate production and joint inflammation. J. Immunol. 203, 3199–3208 (2019).

    CAS  PubMed  Google Scholar 

  161. Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Haak, B. W. et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT. Blood 131, 2978–2986 (2018). This study links the presence of a higher proportion of butyrate-producing faecal microbiota before allogeneic haematopoetic stem cell transplantation with a fivefold lower risk of lower respiratory tract viral infections within the first 6 months after transplant, after adjusting for other risk factors.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Bailin, S. S., Gabriel, C. L., Wanjalla, C. N. & Koethe, J. R. Obesity and weight gain in persons with HIV. Curr HIV/AIDS Rep. 17, 138–150 (2020).

    PubMed  PubMed Central  Google Scholar 

  164. Godfrey, C. et al. Obesity and fat metabolism in human immunodeficiency virus-infected individuals: immunopathogenic mechanisms and clinical implications. J. Infect. Dis. 220, 420–431 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Bourgeois, C. et al. Specific biological features of adipose tissue, and their impact on HIV persistence. Front. Microbiol. 10, 2837 (2019).

    PubMed  PubMed Central  Google Scholar 

  166. Damouche, A. et al. Adipose tissue is a neglected viral reservoir and an inflammatory site during chronic HIV and SIV infection. PLoS Pathog. 11, e1005153 (2015). This paper demonstrates that after infection with simian immunodeficiency virus, the number of adipocytes increases and adipose tissue immune cells become more activated, with the presence of the virus in both CD4+ T cells and macrophages; similarly, sorted CD4+ T cells from human adipose tissue have evidence of HIV-1 infection, thus highlighting an important role of adipose tissue as a viral reservoir.

    PubMed  PubMed Central  Google Scholar 

  167. He, T. et al. High-fat diet exacerbates SIV pathogenesis and accelerates disease progression. J. Clin. Invest. 129, 5474–5488 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Mandrup-Poulsen, T. Immunometabolism in 2017: metabolism and the inflammasome in health and ageing. Nat. Rev. Endocrinol. 14, 72–74 (2018).

    CAS  PubMed  Google Scholar 

  171. Palmer, C. S. et al. Metabolically active CD4+ T cells expressing Glut1 and OX40 preferentially harbor HIV during in vitro infection. FEBS Lett. 591, 3319–3332 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Fromentin, R. et al. CD4+ T cells expressing PD-1, TIGIT and LAG-3 contribute to HIV persistence during ART. PLoS Pathog. 12, e1005761 (2016).

    PubMed  PubMed Central  Google Scholar 

  173. Passaes, C. P. & Saez-Cirion, A. HIV cure research: advances and prospects. Virology 454-455, 340–352 (2014).

    CAS  PubMed  Google Scholar 

  174. 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).

    PubMed  PubMed Central  Google Scholar 

  175. Borsa, M. et al. Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory. Sci Immunol 4, eaav1730 (2019).

    CAS  PubMed  Google Scholar 

  176. Palmer, C. S. et al. Glucose transporter 1-expressing proinflammatory monocytes are elevated in combination antiretroviral therapy-treated and untreated HIV+ subjects. J. Immunol. 193, 5595–5603 (2014). This paper shows a high level of GLUT1 expression on monocytes, predominantly CD16+ subsets, of individuals positive for HIV-1 on antiretroviral therapy compared with healthy controls, and this is associated with higher levels of glucose uptake and lactate production.

    CAS  PubMed  Google Scholar 

  177. Noel, N., Saez-Cirion, A., Avettand-Fenoel, V., Boufassa, F. & Lambotte, O. HIV controllers: to treat or not to treat? Is that the right question? Lancet HIV. 6, e878–e884 (2019).

    PubMed  Google Scholar 

  178. Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).

    CAS  PubMed  Google Scholar 

  179. Routy, J. P. et al. Effect of metformin on the size of the HIV reservoir in non-diabetic ART-treated individuals: single-arm non-randomised Lilac pilot study protocol. BMJ Open. 9, e028444 (2019).

    PubMed  PubMed Central  Google Scholar 

  180. Shikuma, C. M. et al. Metformin reduces CD4 T cell exhaustion in HIV-infected adults on suppressive antiretroviral therapy. AIDS Res Hum Retroviruses 36, 303–305 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. O’Sullivan, D. & Pearce, E. L. Targeting T cell metabolism for therapy. Trends Immunol. 36, 71–80 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Zhao, Y., Butler, E. B. & Tan, M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4, e532 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Li, X. et al. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat. Rev. Clin. Oncol. 16, 425–441 (2019). This Review summarizes challenges and current efforts to target metabolic pathways in anticancer therapeutic strategies.

    CAS  PubMed  Google Scholar 

  184. Anderson, K. G., Stromnes, I. M. & Greenberg, P. D. Obstacles posed by the tumor microenvironment to T cell activity: a case for synergistic therapies. Cancer Cell 31, 311–325 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).

    PubMed  PubMed Central  Google Scholar 

  186. Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Amador-Licona, N. et al. Omega 3 fatty acids supplementation and oxidative stress in HIV-seropositive patients. a clinical trial. PLoS ONE 11, e0151637 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Mukherjee, P. et al. Therapeutic benefit of combining calorie-restricted ketogenic diet and glutamine targeting in late-stage experimental glioblastoma. Commun. Biol. 2, 200 (2019).

    PubMed  PubMed Central  Google Scholar 

  189. Maruvada, P., Leone, V., Kaplan, L. M. & Chang, E. B. The human microbiome and obesity: moving beyond associations. Cell Host Microbe 22, 589–599 (2017).

    CAS  PubMed  Google Scholar 

  190. Tabilas, C. et al. Cutting edge: elevated glycolytic metabolism limits the formation of memory CD8+ T cells in early life. J. Immunol. 203, 2571–2576 (2019). This study shows high dependency of CD8+ T cells on glycolysis after infection, with defective development of CD8+ memory T cell responses in neonatal mice; by contrast, inhibition of glycolysis can potentiate CD8+ memory T cell responses.

    CAS  PubMed  Google Scholar 

  191. Eisenreich, W., Rudel, T., Heesemann, J. & Goebel, W. How viral and intracellular bacterial pathogens reprogram the metabolism of host cells to allow their intracellular replication. Front. Cell Infect. Microbiol. 9, 42 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Ecker, C. & Riley, J. L. Translating in vitro T cell metabolic findings to in vivo tumor models of nutrient competition. Cell Metab. 28, 190–195 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Magalhaes, I., Yogev, O., Mattsson, J. & Schurich, A. The metabolic profile of tumor and virally infected cells shapes their microenvironment counteracting T cell immunity. Front. Immunol. 10, 2309 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Palmer, C. S., Cherry, C. L., Sada-Ovalle, I., Singh, A. & Crowe, S. M. Glucose metabolism in T cells and monocytes: new perspectives in HIV pathogenesis. EBioMedicine 6, 31–41 (2016).

    PubMed  PubMed Central  Google Scholar 

  195. Ohta, A. et al. In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front. Immunol. 2, 27 (2011).

    PubMed  PubMed Central  Google Scholar 

  196. Zenewicz, L. A. Oxygen levels and immunological studies. Front. Immunol. 8, 324 (2017).

    PubMed  PubMed Central  Google Scholar 

  197. Cossarizza, A. & Moyle, G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 18, 137–151 (2004).

    CAS  PubMed  Google Scholar 

  198. Zhao, X. et al. Tenofovir and adefovir down-regulate mitochondrial chaperone TRAP1 and succinate dehydrogenase subunit B to metabolically reprogram glucose metabolism and induce nephrotoxicity. Sci. Rep. 7, 46344 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Venter, W. D. F. et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N. Engl. J. Med. 381, 803–815 (2019).

    CAS  PubMed  Google Scholar 

  200. Masson, J. J. R. et al. Assessment of metabolic and mitochondrial dynamics in CD4+ and CD8+ T cells in virologically suppressed HIV-positive individuals on combination antiretroviral therapy. PLoS ONE 12, e0183931 (2017).

    PubMed  PubMed Central  Google Scholar 

  201. Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank the members of the Sáez-Cirión and Sereti laboratories for discussions. A.S.-C. acknowledges funding from Institut Pasteur (GPF LINMEC programme, project METINFECT), MSDAVENIR, ANRS, Sidaction and amfAR (108687-54-RGRL and 108928-56-RGRL) related to his work on this subject. The work of I.S. was supported by the intramural research programme of the National Institute of Allergy and Infectious Diseases (NIAID)/NIH.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Asier Sáez-Cirión.

Ethics declarations

Competing interests

A.S.-C. is listed as inventor in a patent application submitted by Institut Pasteur based on the potential of metabolic modulators to counteract HIV-1 infection.

Additional information

Peer review information

Nature Reviews Immunology thanks P.-C. Ho, D. Russell and L. Trautmann for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Glycolysis

A metabolic process in which glucose is broken down to obtain energy and carbon products.

Tricarboxylic acid cycle

(TCA cycle; also known as the citric acid cycle or Krebs cycle). A series of chemical reactions that occur in the mitochondria and that transform carbon products into ATP.

Pentose phosphate pathway

(PPP). A pathway of glucose metabolism that parallels glycolysis and generates ribose for the synthesis of nucleotides, amino acids and NADPH.

Fatty acid oxidation

(FAO). The degradation of fatty acids in mitochondria to obtain ATP.

Fatty acid synthesis

(FAS). A metabolic process that uses citrate from the tricarboxylic acid cycle to produce fatty acids and lipid-based structures.

Amino acid metabolism

A metabolic process in which amino acids such as glutamine are broken down to feed the tricarboxylic acid cycle and obtain energy.

Oxidative phosphorylation

(OXPHOS). A process that generates ATP as a result of the transfer of electrons from energy-rich molecules produced in the tricarboxylic acid cycle to oxygen.

Macrophage polarization

The process by which macrophages produce distinct functional phenotypes as a reaction to specific microenvironmental stimuli and signals. ‘M1’ and ‘M2’ are classifications historically used to define macrophages activated in vitro as pro-inflammatory (when ‘classically’ activated with interferon-γ and lipopolysaccharide) or anti-inflammatory (when ‘alternatively’ activated with IL-4 or IL-10), respectively. However, in vivo macrophages are highly specialized, transcriptomically dynamic and extremely heterogeneous with regard to their phenotypes and functions, which are continuously shaped by their tissue microenvironment. Therefore, the M1 or M2 classification is too simplistic to explain the true nature of in vivo macrophages, although these terms are still often used to indicate whether the macrophages in question are more pro-inflammatory or anti-inflammatory.

P-TEFb complex

(Positive transcription elongation factor b complex). A heterodimer of cyclin-dependent kinase 9 and one cyclin T1, cyclin T2 or cyclin K subunit. P-TEFb recruitment to the HIV-1 promoter by the HIV-1 factor Tat is crucial for efficient HIV-1 transcriptional elongation and expression.

Crotonylation

A post-translational modification of histones consisting of the modification of lysine residues by the introduction of crotonyl groups from crotonyl-CoA derived from fatty acid synthesis.

T cell exhaustion

A T cell state that involves loss of effector functions and memory potential as a consequence of persistent stimulation by antigens or activation signals. It is associated with the upregulation of expression of inhibitory receptors such as PD1.

Precursor exhausted T cells

A recently identified subset of T cells that share some characteristics with both classical exhausted T cells and classical memory T cells. They are thought to replenish the pool of exhausted T cells.

Late presenters

Individuals who present for clinical care at an advanced stage of HIV-1 infection, with either very low CD4+ T cell counts or AIDS-defining events.

Immune reconstitution inflammatory syndrome

An aberrant and highly inflammatory response to an existing HIV-1 infection that sometimes occurs during the recovery of the immune system after initiation of antiretroviral therapy.

Shock and kill strategy

A strategy aiming at HIV-1 cure that consists of reactivating latent proviruses from the persistent viral reservoir (shock) so that all infected cells can then be eliminated (kill).

Block and lock strategy

A strategy aiming at HIV-1 remission that consists of reinforcing the mechanisms repressing HIV-1 transcription (block) and increasing the threshold required for reactivation signals (lock), so that latency can be maintained for long periods of time after interruption of antiretroviral therapy.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sáez-Cirión, A., Sereti, I. Immunometabolism and HIV-1 pathogenesis: food for thought. Nat Rev Immunol 21, 5–19 (2021). https://doi.org/10.1038/s41577-020-0381-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-020-0381-7

Further reading

Search

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