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
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Beisel, W. R. Metabolic response to infection. Annu. Rev. Med. 26, 9–20 (1975).
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).
Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).
O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
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).
Waickman, A. T. & Powell, J. D. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol. Rev. 249, 43–58 (2012).
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.
Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
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).
Pallett, L. J., Schmidt, N. & Schurich, A. T cell metabolism in chronic viral infection. Clin. Exp. Immunol. 197, 143–152 (2019).
Sanchez, E. L. & Lagunoff, M. Viral activation of cellular metabolism. Virology 479-480, 609–618 (2015).
Manel, N. et al. The ubiquitous glucose transporter GLUT-1 is a receptor for HTLV. Cell 115, 449–459 (2003).
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).
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).
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).
Appay, V. & Sauce, D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J. Pathol. 214, 231–241 (2008).
Douek, D. C. et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 417, 95–98 (2002).
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).
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).
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).
Buzon, M. J. et al. HIV-1 persistence in CD4+ T cells with stem cell-like properties. Nat. Med. 20, 139–142 (2014).
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).
Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).
Patsoukis, N. et al. The role of metabolic reprogramming in T cell fate and function. Curr. Trends Immunol. 17, 1–12 (2016).
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).
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.
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).
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).
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.
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).
Loisel-Meyer, S. et al. Glut1-mediated glucose transport regulates HIV infection. Proc. Natl Acad. Sci. USA 109, 2549–2554 (2012).
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.
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).
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).
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).
Ganor, Y. et al. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat. Microbiol. 4, 633–644 (2019).
Kruize, Z. & Kootstra, N. A. The role of macrophages in HIV-1 persistence and pathogenesis. Front. Microbiol. 10, 2828 (2019).
Russell, D. G., Huang, L. & VanderVen, B. C. Immunometabolism at the interface between macrophages and pathogens. Nat. Rev. Immunol 19, 291–304 (2019).
Murray, P. J. Macrophage polarization. Annu. Rev. Physiol. 79, 541–566 (2017).
Xue, J. et al. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40, 274–288 (2014).
Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).
Cassol, E., Cassetta, L., Alfano, M. & Poli, G. Macrophage polarization and HIV-1 infection. J. Leukoc. Biol. 87, 599–608 (2010).
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).
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).
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).
Datta, P. K. et al. Glutamate metabolism in HIV-1 infected macrophages: role of HIV-1 Vpr. Cell Cycle. 15, 2288–2298 (2016).
Sen, S. et al. Role of hexokinase-1 in the survival of HIV-1-infected macrophages. Cell Cycle. 14, 980–989 (2015).
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).
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).
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).
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).
Kuo, H. H. et al. Anti-apoptotic protein BIRC5 maintains survival of HIV-1-infected CD4+ T cells. Immunity 48, 1183–1194.e5 (2018).
Lane, A. N. & Fan, T. W. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res. 43, 2466–2485 (2015).
Amie, S. M., Noble, E. & Kim, B. Intracellular nucleotide levels and the control of retroviral infections. Virology 436, 247–254 (2013).
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).
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).
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).
Mathews, C. K. Deoxyribonucleotide metabolism, mutagenesis and cancer. Nat. Rev. Cancer 15, 528–539 (2015).
Descours, B. et al. SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4+ T-cells. Retrovirology 9, 87 (2012).
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.
Goldstone, D. C. et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase. Nature 480, 379–382 (2011).
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).
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).
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).
Coomer, C. A. et al. Single-cell glycolytic activity regulates membrane tension and HIV-1 fusion. PLoS Pathog. 16, e1008359 (2020).
Duran, R. V. et al. Glutaminolysis activates Rag–mTORC1 signaling. Mol. Cell 47, 349–358 (2012).
Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325–338 (2012).
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.
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.
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).
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).
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.
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).
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).
Lochner, M., Berod, L. & Sparwasser, T. Fatty acid metabolism in the regulation of T cell function. Trends Immunol. 36, 81–91 (2015).
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).
Bryant, M. & Ratner, L. Myristoylation-dependent replication and assembly of human immunodeficiency virus 1. Proc. Natl Acad. Sci. USA 87, 523–527 (1990).
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).
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).
Bukrinsky, M. & Sviridov, D. Human immunodeficiency virus infection and macrophage cholesterol metabolism. J. Leukoc. Biol. 80, 1044–1051 (2006).
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).
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).
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).
Jiang, G. et al. HIV latency is reversed by ACSS2-driven histone crotonylation. J. Clin. Invest. 128, 1190–1198 (2018).
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell. 58, 203–215 (2015).
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).
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).
Seror, C. et al. Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection. J. Exp. Med. 208, 1823–1834 (2011).
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).
Barrero, C. A. et al. HIV-1 Vpr modulates macrophage metabolic pathways: a SILAC-based quantitative analysis. PLoS ONE 8, e68376 (2013).
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).
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).
Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570–586 (2017).
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.
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).
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).
Appay, V. et al. Dynamics of T cell responses in HIV infection. J. Immunol. 168, 3660–3666 (2002).
Saez-Cirion, A. & Manel, N. Immune responses to retroviruses. Annu. Rev. Immunol. 36, 193–220 (2018).
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).
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).
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).
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).
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.
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).
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.
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
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).
Hertoghs, K. M. et al. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J. Clin. Invest. 120, 4077–4090 (2010).
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).
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).
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).
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.
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).
Barili, V. et al. Targeting p53 and histone methyltransferases restores exhausted CD8+ T cells in HCV infection. Nat. Commun. 11, 604 (2020).
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).
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.
McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213–221 (2018).
Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).
Kallies, A., Zehn, D. & Utzschneider, D. T. Precursor exhausted T cells: key to successful immunotherapy? Nat. Rev. Immunol. 20, 128–136 (2020).
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).
Zhou, X. et al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33, 229–240 (2010).
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.
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).
Saez-Cirion, A. & Pancino, G. HIV controllers: a genetically determined or inducible phenotype? Immunol. Rev. 254, 281–294 (2013).
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).
Betts, M. R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781–4789 (2006).
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).
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).
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).
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).
Chowdhury, F. Z. et al. Metabolic pathway activation distinguishes transcriptional signatures of CD8+ T cells from HIV-1 elite controllers. AIDS 32, 2669 (2018).
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).
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).
Mueller, Y. M. et al. IL-15 enhances survival and function of HIV-specific CD8+ T cells. Blood 101, 1024–1029 (2003).
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.
Arnoult, D., Petit, F., Lelievre, J. D. & Estaquier, J. Mitochondria in HIV-1-induced apoptosis. Biochem. Biophys. Res. Commun. 304, 561–574 (2003).
Younes, S. A. et al. Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction. J. Clin. Invest. 128, 5083–5094 (2018).
O’Brien, K. L. & Finlay, D. K. Immunometabolism and natural killer cell responses. Nat. Rev. Immunol. 19, 282–290 (2019).
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).
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).
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).
Moir, S. & Fauci, A. S. B-cell responses to HIV infection. Immunol. Rev. 275, 33–48 (2017).
Deeks, S. G., Lewin, S. R. & Havlir, D. V. The end of AIDS: HIV infection as a chronic disease. Lancet 382, 1525–1533 (2013).
Kominsky, D. J., Campbell, E. L. & Colgan, S. P. Metabolic shifts in immunity and inflammation. J. Immunol. 184, 4062–4068 (2010).
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).
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.
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).
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).
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).
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.
Sathekge, M., Maes, A. & Van de Wiele, C. FDG-PET imaging in HIV infection and tuberculosis. Semin. Nucl. Med. 43, 349–366 (2013).
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).
Henrich, T. J., Hsue, P. Y. & VanBrocklin, H. Seeing is believing: nuclear imaging of HIV persistence. Front. Immunol. 10, 2077 (2019).
Cervenka, I., Agudelo, L. Z. & Ruas, J. L. Kynurenines: tryptophan’s metabolites in exercise, inflammation, mental health. Science 357, eaaf9794 (2017).
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).
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).
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.
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).
Guillen, Y. et al. Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection. Mucosal Immunol. 12, 232–246 (2019).
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).
Schulthess, J. et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity 50, 432–445.e7 (2019).
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.
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).
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).
Bourgeois, C. et al. Specific biological features of adipose tissue, and their impact on HIV persistence. Front. Microbiol. 10, 2837 (2019).
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.
He, T. et al. High-fat diet exacerbates SIV pathogenesis and accelerates disease progression. J. Clin. Invest. 129, 5474–5488 (2019).
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).
Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179–188 (2011).
Mandrup-Poulsen, T. Immunometabolism in 2017: metabolism and the inflammasome in health and ageing. Nat. Rev. Endocrinol. 14, 72–74 (2018).
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).
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).
Passaes, C. P. & Saez-Cirion, A. HIV cure research: advances and prospects. Virology 454-455, 340–352 (2014).
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).
Borsa, M. et al. Modulation of asymmetric cell division as a mechanism to boost CD8+ T cell memory. Sci Immunol 4, eaav1730 (2019).
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.
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).
Herzig, S. & Shaw, R. J. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 19, 121–135 (2018).
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).
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).
O’Sullivan, D. & Pearce, E. L. Targeting T cell metabolism for therapy. Trends Immunol. 36, 71–80 (2015).
Zhao, Y., Butler, E. B. & Tan, M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 4, e532 (2013).
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.
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).
DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).
Nencioni, A., Caffa, I., Cortellino, S. & Longo, V. D. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18, 707–719 (2018).
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).
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).
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).
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.
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).
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).
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).
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).
Ohta, A. et al. In vivo T cell activation in lymphoid tissues is inhibited in the oxygen-poor microenvironment. Front. Immunol. 2, 27 (2011).
Zenewicz, L. A. Oxygen levels and immunological studies. Front. Immunol. 8, 324 (2017).
Cossarizza, A. & Moyle, G. Antiretroviral nucleoside and nucleotide analogues and mitochondria. AIDS 18, 137–151 (2004).
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).
Venter, W. D. F. et al. Dolutegravir plus two different prodrugs of tenofovir to treat HIV. N. Engl. J. Med. 381, 803–815 (2019).
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).
Rosen, E. D. & Spiegelman, B. M. What we talk about when we talk about fat. Cell 156, 20–44 (2014).
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
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
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
About this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-020-0381-7
This article is cited by
-
Amino acid metabolism dysregulation associated with inflammation and insulin resistance in HIV-infected individuals with metabolic disorders
Amino Acids (2023)
-
Biological Aging in People Living with HIV on Successful Antiretroviral Therapy: Do They Age Faster?
Current HIV/AIDS Reports (2023)
-
Viral and Host Biomarkers of HIV Remission Post Treatment Interruption
Current HIV/AIDS Reports (2022)
-
Integrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Nature Communications (2021)
