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REVIEW

Glutaminolysis of CD4+ T Cells: A Potential Therapeutic Target in Viral Diseases

, , , &
Pages 603-616 | Received 07 Oct 2023, Accepted 13 Jan 2024, Published online: 01 Feb 2024

References

  • Wik JA, Skålhegg BS. T cell metabolism in infection. Front Immunol. 2022;13:840610. doi:10.3389/fimmu.2022.840610
  • Yu W, Li C, Zhang D, et al. Advances in T cells based on inflammation in metabolic diseases. Cells. 2022;11(22):3554. doi:10.3390/cells11223554
  • Feng X, Li X, Liu N, Hou N, Sun X, Liu Y. Glutaminolysis and CD4(+) T-cell metabolism in autoimmunity: from pathogenesis to therapy prospects. Front Immunol. 2022;13:986847. doi:10.3389/fimmu.2022.986847
  • Kono M. New insights into the metabolism of Th17 cells. Immunol Med. 2023;46(1):15–24. doi:10.1080/25785826.2022.2140503
  • Yang X, Xia R, Yue C, et al. ATF4 regulates CD4(+) T cell immune responses through metabolic reprogramming. Cell Rep. 2018;23(6):1754–1766. doi:10.1016/j.celrep.2018.04.032
  • Parveen S, Shen J, Lun S, et al. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis. bioRxiv. 2023. doi:10.1101/2023.02.23.529704
  • Leone RD, Zhao L, Englert JM, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science. 2019;366(6468):1013–1021. doi:10.1126/science.aav2588
  • Oh MH, Sun IH, Zhao L, et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest. 2020;130(7):3865–3884. doi:10.1172/JCI131859
  • Parveen S, Shen J, Lun S, et al. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis. Nat Commun. 2023;14(1):7427. doi:10.1038/s41467-023-43304-0
  • Clerc I, Moussa DA, Vahlas Z, 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. 2019;1(7):717–730. doi:10.1038/s42255-019-0084-1
  • Loucif H, Dagenais-Lussier X, Avizonis D, et al. Autophagy-dependent glutaminolysis drives superior IL21 production in HIV-1-specific CD4 T cells. Autophagy. 2022;18(6):1256–1273. doi:10.1080/15548627.2021.1972403
  • Chakraborty S, Khamaru P, Bhattacharyya A. Regulation of immune cell metabolism in health and disease: special focus on T and B cell subsets. Cell Biol Int. 2022;46(11):1729–1746. doi:10.1002/cbin.11867
  • Zhang X, Wang G, Bi Y, Jiang Z, Wang X. Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice. Int Immunopharmacol. 2022;112:109133. doi:10.1016/j.intimp.2022.109133
  • Zhao X, Petrashen AP, Sanders JA, Peterson AL, Sedivy JM. SLC1A5 glutamine transporter is a target of MYC and mediates reduced mTORC1 signaling and increased fatty acid oxidation in long-lived Myc hypomorphic mice. Aging Cell. 2019;18(3):e12947. doi:10.1111/acel.12947
  • Ikeda K, Kinoshita M, Kayama H, et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Rep. 2017;21(7):1824–1838. doi:10.1016/j.celrep.2017.10.082
  • Johnson MO, Wolf MM, Madden MZ, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell. 2018;175(7):1780–95.e19. doi:10.1016/j.cell.2018.10.001
  • Liang Y, Su S, Lun Z, et al. Ferroptosis regulator SLC7A11 is a prognostic marker and correlated with PD-L1 and immune cell infiltration in liver hepatocellular carcinoma. Front Mol Biosci. 2022;9:1012505. doi:10.3389/fmolb.2022.1012505
  • Jin J, Kim C, Xia Q, et al. Activation of mTORC1 at late endosomes misdirects T cell fate decision in older individuals. Sci Immunol. 2021;6(60). doi:10.1126/sciimmunol.abg0791
  • Tajima M, Strober W. Evaluation of Glutaminolysis in T Cells. Current Protocols. 2022;2(9):e540. doi:10.1002/cpz1.540
  • Choi SC, Titov AA, Abboud G, et al. Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells. Nat Commun. 2018;9(1):4369. doi:10.1038/s41467-018-06686-0
  • Kim C, Hu B, Jadhav RR, et al. Activation of miR-21-regulated pathways in immune aging selects against signatures characteristic of memory T cells. Cell Rep. 2018;25(8):2148–62.e5. doi:10.1016/j.celrep.2018.10.074
  • Cantor J, Browne CD, Ruppert R, et al. CD98hc facilitates B cell proliferation and adaptive humoral immunity. Nat Immunol. 2009;10(4):412–419. doi:10.1038/ni.1712
  • Bednar KJ, Lee JH, Ort T. Tregs in autoimmunity: insights into intrinsic brake mechanism driving pathogenesis and immune homeostasis. Front Immunol. 2022;13:932485. doi:10.3389/fimmu.2022.932485
  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–787. doi:10.1016/j.cell.2008.05.009
  • Lee J, Kim D, Min B. Tissue Resident Foxp3(+) regulatory T cells: sentinels and saboteurs in health and disease. Front Immunol. 2022;13:865593. doi:10.3389/fimmu.2022.865593
  • Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. 2016;37(11):803–811. doi:10.1016/j.it.2016.08.012
  • Shevach EM, Thornton AM. tTregs, pTregs, and iTregs: similarities and differences. Immunol Rev. 2014;259(1):88–102. doi:10.1111/imr.12160
  • Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014;40(5):692–705. doi:10.1016/j.immuni.2014.04.007
  • Klysz D, Tai X, Robert PA, et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci Signaling. 2015;8(396):ra97. doi:10.1126/scisignal.aab2610
  • Xu T, Stewart KM, Wang X, et al. Metabolic control of T(H)17 and induced T(reg) cell balance by an epigenetic mechanism. Nature. 2017;548(7666):228–233. doi:10.1038/nature23475
  • Carbone F, De Rosa V, Carrieri PB, et al. Regulatory T cell proliferative potential is impaired in human autoimmune disease. Nature Med. 2014;20(1):69–74. doi:10.1038/nm.3411
  • Procaccini C, Garavelli S, Carbone F, et al. Signals of pseudo-starvation unveil the amino acid transporter SLC7A11 as key determinant in the control of Treg cell proliferative potential. Immunity. 2021;54(7):1543–60.e6. doi:10.1016/j.immuni.2021.04.014
  • Liu B, Salgado OC, Singh S, et al. The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nat Commun. 2019;10(1):354. doi:10.1038/s41467-019-08300-3
  • Long Y, Tao H, Karachi A, et al. Dysregulation of glutamate transport enhances treg function that promotes VEGF blockade resistance in glioblastoma. Cancer Res. 2020;80(3):499–509. doi:10.1158/0008-5472.CAN-19-1577
  • Valvo V, Parietti E, Deans K, et al. High-throughput in situ perturbation of metabolite levels in the tumor micro-environment reveals favorable metabolic condition for increased fitness of infiltrated T-cells. Front Cell Develop Biol. 2022;10:1032360. doi:10.3389/fcell.2022.1032360
  • Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17. doi:10.1016/j.cyto.2014.09.011
  • Gomez-Bris R, Saez A, Herrero-Fernandez B, Rius C, Sanchez-Martinez H, Gonzalez-Granado JM. CD4 T-cell subsets and the pathophysiology of inflammatory bowel disease. Int J Mol Sci. 2023;24(3):2696. doi:10.3390/ijms24032696
  • Wang P, Zhang Q, Tan L, Xu Y, Xie X, Zhao Y. The regulatory effects of mTOR complexes in the differentiation and function of CD4(+) T cell subsets. J Immunol Res. 2020;2020:3406032. doi:10.1155/2020/3406032
  • Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14(5):500–508. doi:10.1038/ni.2556
  • Kurihara T, Arimochi H, Bhuyan ZA, et al. CD98 heavy chain is a potent positive regulator of CD4+ T cell proliferation and interferon-γ production in vivo. PLoS One. 2015;10(10):e0139692. doi:10.1371/journal.pone.0139692
  • Cheng X, Wang Y, Liu L, Lv C, Liu C, Xu J. SLC7A11, a potential therapeutic target through induced ferroptosis in colon adenocarcinoma. Front Mol Biosci. 2022;9:889688. doi:10.3389/fmolb.2022.889688
  • Yeh CL, Su LH, Wu JM, et al. Effects of the glutamine administration on T helper cell regulation and inflammatory response in obese mice complicated with polymicrobial sepsis. Mediators Inflammation. 2020;2020:8869017. doi:10.1155/2020/8869017
  • Goretzki A, Zimmermann J, Rainer H, Lin YJ, Schülke S. Immune metabolism in TH2 responses: new opportunities to improve allergy treatment - disease-specific findings (Part 1). Curr Allergy Asthma Rep. 2023;23(1):29–40. doi:10.1007/s11882-022-01057-8
  • Lin YJ, Goretzki A, Rainer H, Zimmermann J, Schülke S. Immune metabolism in TH2 responses: new opportunities to improve allergy treatment - cell type-specific findings (Part 2). Curr Allergy Asthma Rep. 2023;23(1):41–52. doi:10.1007/s11882-022-01058-7
  • Yan L, He J, Liao X, et al. A comprehensive analysis of the diagnostic and prognostic value associated with the SLC7A family members in breast cancer. Gland Surg. 2022;11(2):389–411. doi:10.21037/gs-21-909
  • Hayashi K, Kaminuma O, Nishimura T, et al. LAT1-specific inhibitor is effective against T cell-mediated allergic skin inflammation. Allergy. 2020;75(2):463–467. doi:10.1111/all.14019
  • Hayashi K, Kaminuma O. Therapeutic potential for intractable asthma by targeting L-type amino acid transporter 1. Biomolecules. 2022;12(4):553. doi:10.3390/biom12040553
  • Kaminuma O, Nishimura T, Saeki M, et al. L-type amino acid transporter 1 (LAT1)-specific inhibitor is effective against T cell-mediated nasal hyperresponsiveness. Allergol Int. 2020;69(3):455–458. doi:10.1016/j.alit.2019.12.006
  • Ito D, Miura K, Saeki M, et al. L-type amino acid transporter 1 inhibitor suppresses murine Th2 cell-mediated bronchial hyperresponsiveness independently of eosinophil accumulation. Asia Pac Allergy. 2021;11(3):e33. doi:10.5415/apallergy.2021.11.e33
  • Omenetti S, Bussi C, Metidji A, et al. The intestine harbors functionally distinct homeostatic tissue-resident and inflammatory Th17 cells. Immunity. 2019;51(1):77–89.e6. doi:10.1016/j.immuni.2019.05.004
  • Wu X, Tian J, Wang S. Insight into non-pathogenic Th17 cells in autoimmune diseases. Front Immunol. 2018;9:1112. doi:10.3389/fimmu.2018.01112
  • Ghoreschi K, Laurence A, Yang XP, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature. 2010;467(7318):7318):967–71. doi:10.1038/nature09447
  • Lee Y, Awasthi A, Yosef N, et al. Induction and molecular signature of pathogenic TH17 cells. Nat Immunol. 2012;13(10):991–999. doi:10.1038/ni.2416
  • Esplugues E, Huber S, Gagliani N, et al. Control of TH17 cells occurs in the small intestine. Nature. 2011;475(7357):7357):514–8. doi:10.1038/nature10228
  • Hong HS, Mbah NE, Shan M, et al. OXPHOS promotes apoptotic resistance and cellular persistence in T(H)17 cells in the periphery and tumor microenvironment. Sci Immunol. 2022;7(77):eabm8182. doi:10.1126/sciimmunol.abm8182
  • Yu Q, Tu H, Yin X, et al. Targeting glutamine metabolism ameliorates autoimmune hepatitis via inhibiting T cell activation and differentiation. Front Immunol. 2022;13:880262. doi:10.3389/fimmu.2022.880262
  • Xia X, Cao G, Sun G, et al. GLS1-mediated glutaminolysis unbridled by MALT1 protease promotes psoriasis pathogenesis. J Clin Invest. 2020;130(10):5180–5196. doi:10.1172/JCI129269
  • Ren W, Liu G, Yin J, et al. Amino-acid transporters in T-cell activation and differentiation. Cell Death Dis. 2017;8(3):e2655.
  • Kono M, Yoshida N, Maeda K, Tsokos GC. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc Natl Acad Sci USA. 2018;115(10):2478–2483. doi:10.1073/pnas.1714717115
  • Zhang J, Zhao L, Wang J, et al. Targeting mechanistic target of rapamycin complex 1 restricts proinflammatory T cell differentiation and ameliorates takayasu arteritis. Arthritis Rheumatol. 2020;72(2):303–315. doi:10.1002/art.41084
  • Hisada R, Yoshida N, Orite SYK, et al. Role of glutaminase 2 in promoting CD4+ T cell production of interleukin-2 by supporting antioxidant defense in systemic lupus erythematosus. Arthritis Rheumatol. 2022;74(7):1204–1210. doi:10.1002/art.42112
  • Bystrom J, Taher TE, Henson SM, Gould DJ, Mageed RA. Metabolic requirements of Th17 cells and of B cells: regulation and defects in health and in inflammatory diseases. Front Immunol. 2022;13:990794. doi:10.3389/fimmu.2022.990794
  • Zhou Y, Hu L, Zhang H, et al. Guominkang formula alleviate inflammation in eosinophilic asthma by regulating immune balance of Th1/2 and Treg/Th17 cells. Front Pharmacol. 2022;13:978421. doi:10.3389/fphar.2022.978421
  • Zhu J, Paul WE. Heterogeneity and plasticity of T helper cells. Cell Res. 2010;20(1):4–12. doi:10.1038/cr.2009.138
  • Hirota K, Duarte JH, Veldhoen M, et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol. 2011;12(3):255–263. doi:10.1038/ni.1993
  • Schnell A, Huang L, Singer M, et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell. 2021;184(26):6281–98.e23. doi:10.1016/j.cell.2021.11.018
  • Zhang X, Liu J, Cao X. Metabolic control of T-cell immunity via epigenetic mechanisms. Cell Mol Immunol. 2018;15(3):203–205. doi:10.1038/cmi.2017.115
  • Shikuma CM, Chew GM, Kohorn L, et al. Short communication: metformin reduces CD4 t cell exhaustion in HIV-infected adults on suppressive antiretroviral therapy. AIDS Res Hum Retroviruses. 2020;36(4):303–305.
  • Butterfield TR, Hanna DB, Kaplan RC, et al. Elevated CD4 + T-cell glucose metabolism in HIV+ women with diabetes mellitus. AIDS. 2022;36(10):1327–1336. doi:10.1097/QAD.0000000000003272
  • Crater JM, Nixon DF, Furler O’Brien RL. HIV-1 replication and latency are balanced by mTOR-driven cell metabolism. Front Cell Infect Microbiol. 2022;12:1068436. doi:10.3389/fcimb.2022.1068436
  • Moyo D, Tanthuma G, Cary MS, et al. Cohort study of diabetes in HIV-infected adult patients: evaluating the effect of diabetes mellitus on immune reconstitution. Diabetes Res Clin Pract. 2014;103(3):e34–e36. doi:10.1016/j.diabres.2013.12.042
  • Tong X, Zhao F, Thompson CB. The molecular determinants of de novo nucleotide biosynthesis in cancer cells. Curr Opin Genet Dev. 2009;19(1):32–37. doi:10.1016/j.gde.2009.01.002
  • Benito-Lopez JJ, Marroquin-Muciño M, Perez-Medina M, et al. Partners in crime: the feedback loop between metabolic reprogramming and immune checkpoints in the tumor microenvironment. Front Oncol. 2022;12:1101503. doi:10.3389/fonc.2022.1101503
  • Taylor HE, Calantone N, Lichon D, et al. mTOR overcomes multiple metabolic restrictions to enable HIV-1 reverse transcription and intracellular transport. Cell Rep. 2020;31(12):107810. doi:10.1016/j.celrep.2020.107810
  • Abrahams MR, Joseph SB, Garrett N, et al. The replication-competent HIV-1 latent reservoir is primarily established near the time of therapy initiation. Sci Trans Med. 2019;11(513). doi:10.1126/scitranslmed.aaw5589
  • Cruzat V, Macedo Rogero M, Noel Keane K, Curi R, Newsholme P. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients. 2018;10(11):1564. doi:10.3390/nu10111564
  • Nguyen HTT, Wimmer R, Le VQ, Krarup HB. Metabolic fingerprint of progression of chronic hepatitis B: changes in the metabolome and novel diagnostic possibilities. Metabolomics. 2021;17(2):16. doi:10.1007/s11306-020-01767-y
  • Raniga K, Liang C. Interferons: reprogramming the metabolic network against viral infection. Viruses. 2018;10(1):36. doi:10.3390/v10010036
  • Sumbria D, Berber E, Miller L, Rouse BT. Modulating glutamine metabolism to control viral immuno-inflammatory lesions. Cell Immunol. 2021;370:104450. doi:10.1016/j.cellimm.2021.104450
  • Wang K, Hoshino Y, Dowdell K, et al. Glutamine supplementation suppresses herpes simplex virus reactivation. J Clin Invest. 2017;127(7):2626–2630. doi:10.1172/JCI88990
  • Clark SA, Vazquez A, Furiya K, et al. Rewiring of the host cell metabolome and lipidome during lytic gammaherpesvirus infection is essential for infectious-virus production. J Virol. 2023;97(6):e0050623. doi:10.1128/jvi.00506-23
  • Li T, Zhu Y, Cheng F, Lu C, Jung JU, Gao SJ. Oncogenic Kaposi’s sarcoma-associated herpesvirus upregulates argininosuccinate synthase 1, a rate-limiting enzyme of the citrulline-nitric oxide cycle, to activate the STAT3 pathway and promote growth transformation. J Virol. 2019;93(4):10–128.
  • Sanchez EL, Carroll PA, Thalhofer AB, Lagunoff M, Dittmer DP. Latent KSHV infected endothelial cells are glutamine addicted and require glutaminolysis for survival. PLoS Pathogens. 2015;11(7):e1005052. doi:10.1371/journal.ppat.1005052
  • Zhu Y, Li T, Ramos da Silva S, et al. A critical role of glutamine and asparagine γ-nitrogen in nucleotide biosynthesis in cancer cells hijacked by an oncogenic virus. mBio. 2017;8(4). doi:10.1128/mBio.01179-17
  • Lyu M, Wang S, Gao K, et al. Dissecting the landscape of activated CMV-stimulated CD4+ T cells in humans by linking single-cell RNA-Seq with T-cell receptor sequencing. Front Immunol. 2021;12:779961. doi:10.3389/fimmu.2021.779961
  • Lim EY, Jackson SE, Wills MR. The CD4+ T cell response to human cytomegalovirus in healthy and immunocompromised people. Front Cell Infect Microbiol. 2020;10:202. doi:10.3389/fcimb.2020.00202
  • Jin W, Fang M, Sayin I, et al. Differential CD4+ T-cell cytokine and cytotoxic responses between reactivation and latent phases of herpes zoster infection. Pathog Immun. 2022;7(2):171–188. doi:10.20411/pai.v7i2.560
  • Freeman ML, Burkum CE, Cookenham T, et al. CD4 T cells specific for a latency-associated γ-herpesvirus epitope are polyfunctional and cytotoxic. J Iimmunol. 2014;193(12):5827–5834. doi:10.4049/jimmunol.1302060
  • White DW, Suzanne Beard R, Barton ES. Immune modulation during latent herpesvirus infection. Immunol Rev. 2012;245(1):189–208. doi:10.1111/j.1600-065X.2011.01074.x
  • Spekker-Bosker K, Ufermann CM, Maywald M, et al. hCMV-mediated immune escape mechanisms favor pathogen growth and disturb the immune privilege of the eye. Int J Mol Sci. 2019;20(4):858. doi:10.3390/ijms20040858
  • Schmalzl A, Leupold T, Kreiss L, et al. Interferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection. Nat Commun. 2022;13(1):5730. doi:10.1038/s41467-022-33326-5
  • Kamali AN, Noorbakhsh SM, Hamedifar H, et al. A role for Th1-like Th17 cells in the pathogenesis of inflammatory and autoimmune disorders. Mol Immunol. 2019;105:107–115. doi:10.1016/j.molimm.2018.11.015
  • Suessmuth Y, Mukherjee R, Watkins B, et al. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire. Blood. 2015;125(25):3835–3850. doi:10.1182/blood-2015-03-631853
  • Peng H-Y, Wang L, Das JK, et al. Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase. Sig Transd Target Ther. 2023;8(1):415. doi:10.1038/s41392-023-01648-5
  • Preglej T, Ellmeier W. CD4(+) cytotoxic T cells - phenotype, function and transcriptional networks controlling their differentiation pathways. Immunol Lett. 2022;247:27–42. doi:10.1016/j.imlet.2022.05.001
  • Uyangaa E, Lee HK, Eo SK. Glutamine and leucine provide enhanced protective immunity against mucosal infection with herpes simplex virus type 1. Immun Net. 2012;12(5):196–206. doi:10.4110/in.2012.12.5.196
  • Hu YM, Yeh CL, Pai MH, Lee WY, Yeh SL. Glutamine administration modulates lung γδ T lymphocyte expression in mice with polymicrobial sepsis. Shock. 2014;41(2):115–122. doi:10.1097/SHK.0000000000000086
  • Valle-Casuso JC, Angin M, Volant S, 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. 2019;29(3):611–26.e5. doi:10.1016/j.cmet.2018.11.015
  • Deeks SG, Lewin SR, Ross AL, et al. International AIDS Society global scientific strategy: towards an HIV cure 2016. Nature Med. 2016;22(8):839–850. doi:10.1038/nm.4108
  • Taylor HE, Palmer CS. CD4 T cell metabolism is a major contributor of HIV infectivity and reservoir persistence. Immunometabolism. 2020;2(1). doi:10.20900/immunometab20200005
  • Guo H, Wang Q, Ghneim K, et al. Multi-omics analyses reveal that HIV-1 alters CD4+ T cell immunometabolism to fuel virus replication. Nat Immunol. 2021;22(4):423–433. doi:10.1038/s41590-021-00898-1
  • Gubser C, Pitman MC, Lewin SR. CD4+ T cell signatures in HIV infection. Nat Immunol. 2019;20(8):948–950. doi:10.1038/s41590-019-0447-5
  • Fenwick C, Joo V, Jacquier P, et al. T-cell exhaustion in HIV infection. Immunol Rev. 2019;292(1):149–163. doi:10.1111/imr.12823
  • Chan YT, Cheong HC, Tang TF, et al. Immune checkpoint molecules and glucose metabolism in HIV-induced T cell exhaustion. Biomedicines. 2022;10(11):2809. doi:10.3390/biomedicines10112809
  • Plana M, García F, Gallart T, et al. Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection. AIDS. 2000;14(13):1921–1933. doi:10.1097/00002030-200009080-00007
  • Martin GE, Sen DR, Pace M, et al. Epigenetic features of HIV-induced T-cell exhaustion persist despite early antiretroviral therapy. Front Immunol. 2021;12:647688. doi:10.3389/fimmu.2021.647688
  • Gangcuangco LMA, Mitchell BI, Siriwardhana C, et al. Mitochondrial oxidative phosphorylation in peripheral blood mononuclear cells is decreased in chronic HIV and correlates with immune dysregulation. PLoS One. 2020;15(4):e0231761. doi:10.1371/journal.pone.0231761
  • Vellas C, Nayrac M, Collercandy N, et al. Intact proviruses are enriched in the colon and associated with PD-1(+)TIGIT(-) mucosal CD4(+) T cells of people with HIV-1 on antiretroviral therapy. EBioMedicine. 2023;100:104954. doi:10.1016/j.ebiom.2023.104954
  • Benito JM, Restrepo C, García-Foncillas J, Rallón N. Immune checkpoint inhibitors as potential therapy for reverting T-cell exhaustion and reverting HIV latency in people living with HIV. Front Immunol. 2023;14:1270881. doi:10.3389/fimmu.2023.1270881
  • Caetano DG, De Paula HHS, Bello G, et al. HIV-1 elite controllers present a high frequency of activated regulatory T and Th17 cells. PLoS One. 2020;15(2):e0228745. doi:10.1371/journal.pone.0228745
  • Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168(6):960–976. doi:10.1016/j.cell.2017.02.004
  • Ueda Y, Saegusa J, Okano T, et al. Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice. Sci Rep. 2019;9(1):6374. doi:10.1038/s41598-019-42932-1
  • Li JZ, Aga E, Bosch RJ, et al. Time to viral rebound after interruption of modern antiretroviral therapies. Clinl Infect Dis. 2022;74(5):865–870. doi:10.1093/cid/ciab541
  • Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4(1):18035. doi:10.1038/nrdp.2018.35
  • Manns MP, Maasoumy B. Breakthroughs in hepatitis C research: from discovery to cure. Nat Rev Gastroenterol Hepatol. 2022;19(8):533–550.
  • Lopez-Scarim J, Nambiar SM, Billerbeck E. Studying T cell responses to hepatotropic viruses in the liver microenvironment. Vaccines. 2023;11(3):681. doi:10.3390/vaccines11030681
  • Chen J, Wang R, Liu Z, et al. Unbalanced glutamine partitioning between CD8T cells and cancer cells accompanied by immune cell dysfunction in hepatocellular carcinoma. Cells. 2022;11(23):3924. doi:10.3390/cells11233924
  • Baxter VK, Glowinski R, Braxton AM, Potter MC, Slusher BS, Griffin DE. Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis. Virology. 2017;508:134–149. doi:10.1016/j.virol.2017.05.013
  • Sun J, Tumurbaatar B, Jia J, et al. Parenchymal expression of CD86/B7.2 contributes to hepatitis C virus-related liver injury. J Virol. 2005;79(16):10730–10739. doi:10.1128/JVI.79.16.10730-10739.2005
  • Correia MP, Cardoso EM, Pereira CF, Neves R, Uhrberg M, Arosa FA. Hepatocytes and IL-15: a favorable microenvironment for T cell survival and CD8+ T cell differentiation. J Iimmunol. 2009;182(10):6149–6159. doi:10.4049/jimmunol.0802470
  • Huang BY, Tsai MR, Hsu JK, et al. Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma. Mol Carcinogen. 2020;59(11):1269–1279. doi:10.1002/mc.23255
  • Yu Z, Li J, Ren Z, et al. Switching from fatty acid oxidation to glycolysis improves the outcome of acute-on-chronic liver failure. Adv Sci. 2020;7(7):1902996. doi:10.1002/advs.201902996
  • Helling G, Wahlin S, Smedberg M, et al. Plasma glutamine concentrations in liver failure. PLoS One. 2016;11(3):e0150440. doi:10.1371/journal.pone.0150440
  • Raziorrouh B, Heeg M, Kurktschiev P, et al. Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules. PLoS One. 2014;9(8):e105703. doi:10.1371/journal.pone.0105703
  • Raziorrouh B, Ulsenheimer A, Schraut W, et al. Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection. Gastroenterology. 2011;141(4):1422–31, 31.e1–6. doi:10.1053/j.gastro.2011.07.004
  • Ye B, Liu X, Li X, Kong H, Tian L, Chen Y. T-cell exhaustion in chronic hepatitis B infection: current knowledge and clinical significance. Cell Death Dis. 2015;6(3):e1694. doi:10.1038/cddis.2015.42
  • Kaushik AK, Tarangelo A, Boroughs LK, et al. In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Sci Adv. 2022;8(50):eabp8293. doi:10.1126/sciadv.abp8293
  • Rais R, Lemberg KM, Tenora L, et al. Discovery of DRP-104, a tumor-targeted metabolic inhibitor prodrug. Sci Adv. 2022;8(46):eabq5925. doi:10.1126/sciadv.abq5925
  • Cederkvist H, Kolan SS, Wik JA, Sener Z, Skålhegg BS. Identification and characterization of a novel glutaminase inhibitor. FEBS Open Bio. 2022;12(1):163–174. doi:10.1002/2211-5463.13319
  • Al-Dujaili LJ, Clerkin PP, Clement C, et al. Ocular herpes simplex virus: how are latency, reactivation, recurrent disease and therapy interrelated? Future Microbiol. 2011;6(8):877–907. doi:10.2217/fmb.11.73
  • Monteiro FR, Roseira T, Amaral JB, et al. Combined exercise training and l-glutamine supplementation enhances both humoral and cellular immune responses after influenza virus vaccination in elderly subjects. Vaccines. 2020;8(4):685. doi:10.3390/vaccines8040685
  • Howden AJM, Hukelmann JL, Brenes A, et al. Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation. Nat Immunol. 2019;20(11):1542–1554. doi:10.1038/s41590-019-0495-x
  • Pacheco R, Oliva H, Martinez-Navío JM, et al. Glutamate released by dendritic cells as a novel modulator of T cell activation. J Iimmunol. 2006;177(10):6695–6704. doi:10.4049/jimmunol.177.10.6695
  • Arensman MD, Yang XS, Leahy DM, et al. Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc Natl Acad Sci USA. 2019;116(19):9533–9542. doi:10.1073/pnas.1814932116