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MDSC expansion during HIV infection: regulators, ART and immune reconstitution

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Abstract

Myeloid-derived suppressor cells (MDSCs) become expanded in different pathological conditions including human immunodeficiency virus (HIV) infection and this may worsen the disease status and accelerate disease progression. In HIV infection, MDSCs suppress anti-HIV immune responses and hamper immune reconstitution. Understanding the factors and mechanisms of MDSC expansion during HIV infection is central to understanding the pathophysiology of HIV infection. This may pave the way to developing new therapeutic targets or strategies. In this work we addressed (i) the mechanisms that regulate MDSC expansion, (ii) the impact of antiretroviral therapy (ART) on the frequency of MDSCs during HIV infection; (iii) the impact of MDSCs on immune reconstitution during successful ART; and (iv) the potential of MDSCs as a therapeutic target.

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Fig. 1: A proposed scenario describing MDSC expansion during HIV infection.

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References

  1. Marini O, Costa S, Bevilacqua D, Calzetti F, Tamassia N, Spina C, et al. Mature CD10(+) and immature CD10(-) neutrophils present in G-CSF-treated donors display opposite effects on T cells. Blood. 2017;129:1343–56.

    Article  CAS  PubMed  Google Scholar 

  2. Marini O, Spina C, Mimiola E, Cassaro A, Malerba G, Todeschini G, et al. Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget. 2016;7:27676–88.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Carmona-Rivera C, Kaplan MJ. Low-density granulocytes: a distinct class of neutrophils in systemic autoimmunity. Semin Immunopathol. 2013;35:455–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lang S, Bruderek K, Kaspar C, Hoing B, Kanaan O, Dominas N, et al. Clinical relevance and suppressive capacity of human myeloid-derived suppressor cell subsets. Clin Cancer Res. 2018;24:4834–44.

    Article  CAS  PubMed  Google Scholar 

  5. Bergenfelz C, Larsson AM, von Stedingk K, Gruvberger-Saal S, Aaltonen K, Jansson S, et al. Systemic monocytic-MDSCs are generated from monocytes and correlate with disease progression in breast cancer patients. PLoS One. 2015;10:e0127028.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R. Immature immunosuppressive CD14 + HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res. 2010;70:4335–45.

    Article  CAS  PubMed  Google Scholar 

  7. Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30:475–87.

    Article  CAS  PubMed  Google Scholar 

  8. Pillay J, Tak T, Kamp VM, Koenderman L. Immune suppression by neutrophils and granulocytic myeloid-derived suppressor cells: similarities and differences. Cell Mol Life Sci. 2013;70:3813–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Obermajer N, Muthuswamy R, Lesnock J, Edwards RP, Kalinski P. Positive feedback between PGE2 and COX2 redirects the differentiation of human dendritic cells toward stable myeloid-derived suppressor cells. Blood. 2011;118:5498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Domenis R, Cesselli D, Toffoletto B, Bourkoula E, Caponnetto F, Manini I, et al. Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells. PLoS One. 2017;12:e0169932.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Obermajer N, Kalinski P. Generation of myeloid-derived suppressor cells using prostaglandin E2. Transpl Res. 2012;1:15.

    Article  CAS  Google Scholar 

  12. Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Recent advances in myeloid-derived suppressor cell biology. Front Med. 2020;15:232–51.

  13. Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol. 2020;10:200111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dorhoi A, Kotze LA, Berzofsky JA, Sui Y, Gabrilovich DI, Garg A, et al. Therapies for tuberculosis and AIDS: myeloid-derived suppressor cells in focus. J Clin Invest. 2020;130:2789–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cassetta L, Bruderek K, Skrzeczynska-Moncznik J, Osiecka O, Hu X, Rundgren IM, et al. Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation. J Immunother Cancer. 2020;8:e001223.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Schrijver IT, Theroude C, Roger T. Myeloid-derived suppressor cells in sepsis. Front Immunol. 2019;10:327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Li X, Liu J, Xing Z, Tang J, Sun H, Zhang X, et al. Polymorphonuclear myeloid-derived suppressor cells link inflammation and damage response after trauma. J Leukoc Biol. 2021;110:1143–61.

    Article  CAS  PubMed  Google Scholar 

  18. Sun SN, Ni SH, Li Y, Liu X, Deng JP, Chen ZX, et al. G-MDSCs promote aging-related cardiac fibrosis by activating myofibroblasts and preventing senescence. Cell Death Dis. 2021;12:594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li C, Zhang X, Kang X, Chen C, Guo F, Wang Q, et al. Upregulated TRAIL and reduced DcR2 mediate apoptosis of decidual PMN-MDSC in unexplained recurrent pregnancy loss. Front Immunol. 2020;11:1345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kostlin-Gille N, Flaig LA, Ginzel M, Arand J, Poets CF, Gille C. Granulocytic myeloid-derived suppressor cells in breast milk (BM-MDSC) correlate with gestational age and postnatal age and are influenced by infant’s sex. Nutrients. 2020;12:2571.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yaseen MM, Abuharfeil NM, Darmani H. Myeloid-derived suppressor cells and the pathogenesis of human immunodeficiency virus infection. Open Biol. 2021;11:210216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yaseen MM, Abuharfeil NM, Darmani H. The impact of MDSCs on the efficacy of preventive and therapeutic HIV vaccines. Cell Immunol. 2021;369:104440.

    Article  CAS  PubMed  Google Scholar 

  23. Yaseen MM, Abuharfeil NM, Homa D. Anatomical distribution of myeloid-derived suppressor cells during HIV infection. Viral Immunol. 2021;34:673–8.

    Article  CAS  PubMed  Google Scholar 

  24. Tumino N, Bilotta MT, Pinnetti C, Ammassari A, Antinori A, Turchi F, et al. Granulocytic myeloid-derived suppressor cells increased in early phases of primary HIV infection depending on TRAIL plasma level. J Acquir Immune Defic Syndr. 2017;74:575–82.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang ZN, Yi N, Zhang TW, Zhang LL, Wu X, Liu M, et al. Myeloid-derived suppressor cells associated with disease progression in primary HIV infection: PD-L1 blockade attenuates inhibition. J Acquir Immune Defic Syndr. 2017;76:200–8.

    Article  PubMed  Google Scholar 

  26. Agrati C, Tumino N, Bordoni V, Pinnetti C, Sabatini A, Amendola A, et al. Myeloid derived suppressor cells expansion persists after early ART and may affect CD4 T cell recovery. Front Immunol. 2019;10:1886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Qin A, Cai W, Pan T, Wu K, Yang Q, Wang N, et al. Expansion of monocytic myeloid-derived suppressor cells dampens T cell function in HIV-1-seropositive individuals. J Virol. 2013;87:1477–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Vollbrecht T, Stirner R, Tufman A, Roider J, Huber RM, Bogner JR, et al. Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells. AIDS. 2012;26:F31–7.

    Article  CAS  PubMed  Google Scholar 

  29. Garg A, Spector SA. HIV type 1 gp120-induced expansion of myeloid derived suppressor cells is dependent on interleukin 6 and suppresses immunity. J Infect Dis. 2014;209:441–51.

    Article  CAS  PubMed  Google Scholar 

  30. Wang L, Zhao J, Ren JP, Wu XY, Morrison ZD, Elgazzar MA, et al. Expansion of myeloid-derived suppressor cells promotes differentiation of regulatory T cells in HIV-1+ individuals. AIDS. 2016;30:1521–31.

    Article  CAS  PubMed  Google Scholar 

  31. Bowers NL, Helton ES, Huijbregts RP, Goepfert PA, Heath SL, Hel Z. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathog. 2014;10:e1003993.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tumino N, Turchi F, Meschi S, Lalle E, Bordoni V, Casetti R, et al. In HIV-positive patients, myeloid-derived suppressor cells induce T-cell anergy by suppressing CD3zeta expression through ELF-1 inhibition. AIDS. 2015;29:2397–407.

    Article  CAS  PubMed  Google Scholar 

  33. Yaseen MM, Abuharfeil NM, Yaseen MM, Shabsoug BM. The role of polymorphonuclear neutrophils during HIV-1 infection. Arch Virol. 2018;163:1–21.

    Article  CAS  PubMed  Google Scholar 

  34. Alqudah MAY, Yaseen MMM, Yaseen MMS. HIV-1 strategies to overcome the immune system by evading and invading innate immune system. HIV AIDS Rev. 2016;15:1–12.

    Article  Google Scholar 

  35. Abuharfeil NM, Yaseen MM, Alsheyab FM. Harnessing antibody-dependent cellular cytotoxicity to control HIV-1 infection. ACS Infect Dis. 2019;5:158–76.

    Article  CAS  PubMed  Google Scholar 

  36. Yaseen MM, Yaseen MM, Alqudah MA. Broadly neutralizing antibodies: An approach to control HIV-1 infection. Int Rev Immunol. 2017;36:31–40.

    Article  CAS  PubMed  Google Scholar 

  37. Yaseen MM, Abuharfeil NM, Darmani H. The role of IL-1beta during human immunodeficiency virus type 1 infection. Rev Med Virol. 2023;33:e2400.

    Article  CAS  PubMed  Google Scholar 

  38. Yaseen MM, Abuharfeil NM, Darmani H. The role of p53 in HIV infection. Curr HIV/AIDS Rep. 2023;20:419–27.

    Article  PubMed  Google Scholar 

  39. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV. Elevated CD38 antigen expression on CD8 + T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;16:83–92.

    Article  CAS  PubMed  Google Scholar 

  40. Sherman GG, Scott LE, Galpin JS, Kuhn L, Tiemessen CT, Simmank K, et al. CD38 expression on CD8(+) T cells as a prognostic marker in vertically HIV-infected pediatric patients. Pediatr Res. 2002;51:740–5.

    Article  PubMed  Google Scholar 

  41. Hoffmann M, Pantazis N, Martin GE, Hickling S, Hurst J, Meyerowitz J, et al. Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection. PLoS Pathog. 2016;12:e1005661.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhang J, Thakuri BKC, Zhao J, Nguyen LN, Nguyen LNT, Cao D, et al. Long noncoding RNA HOTAIRM1 promotes myeloid-derived suppressor cell expansion and suppressive functions through up-regulating HOXA1 expression during latent HIV infection. AIDS. 2020;34:2211–21.

    Article  CAS  PubMed  Google Scholar 

  43. Namdev P, Patel S, Sparling B, Garg A. Monocytic-myeloid derived suppressor cells of HIV-infected individuals with viral suppression exhibit suppressed innate immunity to mycobacterium tuberculosis. Front Immunol. 2021;12:647019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Paiardini M, Muller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev. 2013;254:78–101.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Guo C, Hu F, Yi H, Feng Z, Li C, Shi L, et al. Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis. Ann Rheum Dis. 2016;75:278–85.

    Article  CAS  PubMed  Google Scholar 

  46. Zhang H, Wang S, Huang Y, Wang H, Zhao J, Gaskin F, et al. Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin Immunol. 2015;157:175–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu H, Zhen Y, Ma Z, Li H, Yu J, Xu ZG, et al. Arginase-1-dependent promotion of TH17 differentiation and disease progression by MDSCs in systemic lupus erythematosus. Sci Transl Med. 2016;8:331ra40.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mukherjee S, Ghosh S, Sengupta A, Sarkar S, Keswani T, Chatterjee R, et al. IL-6 dependent expansion of inflammatory MDSCs (CD11b+ Gr-1+) promote Th-17 mediated immune response during experimental cerebral malaria. Cytokine. 2022;155:155910.

    Article  CAS  PubMed  Google Scholar 

  49. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007;67:10019–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182:4499–506.

    Article  CAS  PubMed  Google Scholar 

  51. Garg A. Analysis of antimicrobial activity of monocytic myeloid-derived suppressor cells in infection with mycobacterium tuberculosis and human immunodeficiency virus. Methods Mol Biol. 2021;2236:115–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lei AH, Yang Q, Cai WP, Liu YF, Lan Y, Qin AP, et al. Clinical significance of myeloid-derived suppressor cells in human immunodeficiency virus-1/ Hepatitis C virus-coinfected patients. Scand J Immunol. 2016;83:438–44.

    Article  CAS  PubMed  Google Scholar 

  53. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011;32:19–25.

    Article  CAS  PubMed  Google Scholar 

  54. Condamine T, Mastio J, Gabrilovich DI. Transcriptional regulation of myeloid-derived suppressor cells. J Leukoc Biol. 2015;98:913–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dufait I, Schwarze JK, Liechtenstein T, Leonard W, Jiang H, Escors D, et al. Ex vivo generation of myeloid-derived suppressor cells that model the tumor immunosuppressive environment in colorectal cancer. Oncotarget. 2015;6:12369–82.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Casacuberta-Serra S, Pares M, Golbano A, Coves E, Espejo C, Barquinero J. Myeloid-derived suppressor cells can be efficiently generated from human hematopoietic progenitors and peripheral blood monocytes. Immunol Cell Biol. 2017;95:538–48.

    Article  CAS  PubMed  Google Scholar 

  58. Mao Y, Poschke I, Wennerberg E, Pico de Coana Y, Egyhazi Brage S, Schultz I, et al. Melanoma-educated CD14+ cells acquire a myeloid-derived suppressor cell phenotype through COX-2-dependent mechanisms. Cancer Res. 2013;73:3877–87.

    Article  CAS  PubMed  Google Scholar 

  59. Rodrigues JC, Gonzalez GC, Zhang L, Ibrahim G, Kelly JJ, Gustafson MP, et al. Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties. Neuro Oncol. 2010;12:351–65.

    Article  CAS  PubMed  Google Scholar 

  60. Moses K, Brandau S. Human neutrophils: their role in cancer and relation to myeloid-derived suppressor cells. Semin Immunol. 2016;28:187–96.

    Article  CAS  PubMed  Google Scholar 

  61. Millrud CR, Bergenfelz C, Leandersson K. On the origin of myeloid-derived suppressor cells. Oncotarget 2017;8:3649–65.

    Article  PubMed  Google Scholar 

  62. Xiu B, Lin Y, Grote DM, Ziesmer SC, Gustafson MP, Maas ML, et al. IL-10 induces the development of immunosuppressive CD14( + )HLA-DR(low/-) monocytes in B-cell non-Hodgkin lymphoma. Blood. Cancer J. 2015;5:e328.

    CAS  Google Scholar 

  63. Abad C, Nobuta H, Li J, Kasai A, Yong WH, Waschek JA. Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J Leukoc Biol. 2014;95:357–67.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tu SP, Jin H, Shi JD, Zhu LM, Suo Y, Lu G, et al. Curcumin induces the differentiation of myeloid-derived suppressor cells and inhibits their interaction with cancer cells and related tumor growth. Cancer Prev Res (Philos). 2012;5:205–15.

    Article  CAS  Google Scholar 

  65. Abrams SI, Netherby CS, Twum DY, Messmer MN. Relevance of interferon regulatory factor-8 expression in myeloid-tumor interactions. J Interferon Cytokine Res. 2016;36:442–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Youn JI, Kumar V, Collazo M, Nefedova Y, Condamine T, Cheng P, et al. Epigenetic silencing of retinoblastoma gene regulates pathologic differentiation of myeloid cells in cancer. Nat Immunol. 2013;14:211–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Casbon AJ, Reynaud D, Park C, Khuc E, Gan DD, Schepers K, et al. Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils. Proc Natl Acad Sci USA. 2015;112:E566–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dai J, Kumbhare A, Williams DA, Youssef D, Yao ZQ, McCall CE, et al. Nfia deletion in myeloid cells blocks expansion of myeloid-derived suppressor cells during sepsis. Innate Immun. 2018;24:54–65.

    Article  CAS  PubMed  Google Scholar 

  69. Tian X, Tian J, Tang X, Rui K, Zhang Y, Ma J, et al. Particulate beta-glucan regulates the immunosuppression of granulocytic myeloid-derived suppressor cells by inhibiting NFIA expression. Oncoimmunology. 2015;4:e1038687.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Zheng Y, Tian X, Wang T, Xia X, Cao F, Tian J, et al. Long noncoding RNA Pvt1 regulates the immunosuppression activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Mol Cancer. 2019;18:61.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kostlin-Gille N, Dietz S, Schwarz J, Spring B, Pauluschke-Frohlich J, Poets CF, et al. HIF-1alpha-deficiency in myeloid cells leads to a disturbed accumulation of myeloid derived suppressor cells (MDSC) during pregnancy and to an increased abortion rate in mice. Front Immunol. 2019;10:161.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI, Cheng P, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J Exp Med. 2010;207:2439–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. van der Veeken J, Gonzalez AJ, Cho H, Arvey A, Hemmers S, Leslie CS, et al. Memory of inflammation in regulatory T cells. Cell 2016;166:977–90.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Rajendeeran A, Tenbrock K. Regulatory T cell function in autoimmune disease. J Transl Autoimmun. 2021;4:100130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Romano M, Fanelli G, Tan N, Nova-Lamperti E, McGregor R, Lechler RI, et al. Expanded regulatory T cells induce alternatively activated monocytes with a reduced capacity to expand T Helper-17 cells. Front Immunol. 2018;9:1625.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Dross SE, Munson PV, Kim SE, Bratt DL, Tunggal HC, Gervassi AL, et al. Kinetics of myeloid-derived suppressor cell frequency and function during simian immunodeficiency virus infection, combination antiretroviral therapy, and treatment interruption. J Immunol. 2017;198:757–66.

    Article  CAS  PubMed  Google Scholar 

  77. Rychert J, Strick D, Bazner S, Robinson J, Rosenberg E. Detection of HIV gp120 in plasma during early HIV infection is associated with increased proinflammatory and immunoregulatory cytokines. AIDS Res Hum Retroviruses. 2010;26:1139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Sharma V, Sachdeva N, Gupta V, Nada R, Jacob J, Sahni D, et al. IL‐6 is associated with expansion of myeloid‐derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients. Scand J Immunol. 2021;94:e13107.

    Article  CAS  PubMed  Google Scholar 

  79. Zheng Z, Zheng X, Zhu Y, Yao Z, Zhao W, Zhu Y, et al. IL-6 promotes the proliferation and immunosuppressive function of myeloid-derived suppressor cells via the MAPK signaling pathway in bladder cancer. Biomed Res Int. 2021;2021:5535578.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Bitsch R, Kurzay A, Ozbay Kurt F, De La Torre C, Lasser S, Lepper A, et al. STAT3 inhibitor Napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice. J Immunother Cancer. 2022;10:e004384.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Klasse PJ, Moore JP. Is there enough gp120 in the body fluids of HIV-1-infected individuals to have biologically significant effects? Virology. 2004;323:1–8.

    Article  CAS  PubMed  Google Scholar 

  82. Gilbert M, Kirihara J, Mills J. Enzyme-linked immunoassay for human immunodeficiency virus type 1 envelope glycoprotein 120. J Clin Microbiol. 1991;29:142–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. King Quinton O, Lei B, Harmsen Allen G. Reply to Eisenhut. J Infect Dis. 2010;201:1273.

    Article  Google Scholar 

  84. Rayne F, Debaisieux S, Bonhoure A, Beaumelle B. HIV-1 Tat is unconventionally secreted through the plasma membrane. Cell Biol Int. 2010;34:409–13.

    Article  CAS  PubMed  Google Scholar 

  85. Zhong Y, Hennig B, Toborek M. Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells. J Cereb Blood Flow Metab. 2010;30:522–33.

    Article  CAS  PubMed  Google Scholar 

  86. Xiao H, Neuveut C, Tiffany HL, Benkirane M, Rich EA, Murphy PM, et al. Selective CXCR4 antagonism by Tat: implications for in vivo expansion of coreceptor use by HIV-1. Proc Natl Acad Sci USA. 2000;97:11466–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Park MY, Lim BG, Kim SY, Sohn HJ, Kim S, Kim TG. GM-CSF promotes the expansion and differentiation of cord blood myeloid-derived suppressor cells, which attenuate xenogeneic graft-vs.-host disease. Front Immunol. 2019;10:183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ma N, Liu Q, Hou L, Wang Y, Liu Z. MDSCs are involved in the protumorigenic potentials of GM-CSF in colitis-associated cancer. Int J Immunopathol Pharm. 2017;30:152–62.

    Article  CAS  Google Scholar 

  89. Priceputu E, Cool M, Bouchard N, Caceres-Cortes JR, Lowell CA, Hanna Z, et al. HIV-1 Nef Induces Hck/Lyn-dependent expansion of myeloid-derived suppressor cells associated with elevated interleukin-17/G-CSF levels. J Virol. 2021;95:e0047121.

    Article  PubMed  Google Scholar 

  90. Campillo-Gimenez L, Cumont MC, Fay M, Kared H, Monceaux V, Diop O, et al. AIDS progression is associated with the emergence of IL-17-producing cells early after simian immunodeficiency virus infection. J Immunol. 2010;184:984–92.

    Article  CAS  PubMed  Google Scholar 

  91. Zizza A, Guido M, Grima P. Interleukin-17 regulates visceral obesity in HIV-1-infected patients. HIV Med. 2012;13:574–7.

    Article  CAS  PubMed  Google Scholar 

  92. He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J Immunol. 2010;184:2281–8.

    Article  CAS  PubMed  Google Scholar 

  93. Gomes AL, Teijeiro A, Buren S, Tummala KS, Yilmaz M, Waisman A, et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2016;30:161–75.

    Article  CAS  PubMed  Google Scholar 

  94. Yazawa T, Shibata M, Gonda K, Machida T, Suzuki S, Kenjo A, et al. Increased IL-17 production correlates with immunosuppression involving myeloid-derived suppressor cells and nutritional impairment in patients with various gastrointestinal cancers. Mol Clin Oncol. 2013;1:675–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen X, Churchill MJ, Nagar KK, Tailor YH, Chu T, Rush BS, et al. IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer. Oncotarget. 2015;6:32966–79.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, et al. Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Invest. 2012;122:974–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Yuan L, Qiao L, Wei F, Yin J, Liu L, Ji Y, et al. Cytokines in CSF correlate with HIV-associated neurocognitive disorders in the post-HAART era in China. J Neurovirol. 2013;19:144–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Shebl FM, Yu K, Landgren O, Goedert JJ, Rabkin CS. Increased levels of circulating cytokines with HIV-related immunosuppression. AIDS Res Hum Retroviruses. 2012;28:809–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Kowanetz M, Wu X, Lee J, Tan M, Hagenbeek T, Qu X, et al. Granulocyte-colony stimulating factor promotes lung metastasis through mobilization of Ly6G + Ly6C+ granulocytes. Proc Natl Acad Sci USA. 2010;107:21248–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Waight JD, Hu Q, Miller A, Liu S, Abrams SI. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism. PLoS One. 2011;6:e27690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Trible RP, Emert-Sedlak L, Smithgall TE. HIV-1 Nef selectively activates Src family kinases Hck, Lyn, and c-Src through direct SH3 domain interaction. J Biol Chem. 2006;281:27029–38.

    Article  CAS  PubMed  Google Scholar 

  102. Tian X, Ma J, Wang T, Tian J, Zhang Y, Mao L, et al. Long non-coding RNA HOXA transcript antisense RNA myeloid-specific 1-HOXA1 axis downregulates the immunosuppressive activity of myeloid-derived suppressor cells in lung cancer. Front Immunol. 2018;9:473.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Thakuri BKC, Zhang J, Zhao J, Nguyen LN, Nguyen LNT, Khanal S, et al. LncRNA HOTAIRM1 promotes MDSC expansion and suppressive functions through the HOXA1-miR124 axis during HCV infection. Sci Rep. 2020;10:22033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M, et al. A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood. 2009;113:2526–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhang J, Thakuri BKC, Zhao J, Nguyen LN, Nguyen LNT, Khanal S, et al. Long noncoding RNA RUNXOR promotes myeloid-derived suppressor cell expansion and functions via enhancing immunosuppressive molecule expressions during latent HIV infection. J Immunol. 2021;206:2052–60.

    Article  CAS  PubMed  Google Scholar 

  106. Marigo I, Bosio E, Solito S, Mesa C, Fernandez A, Dolcetti L, et al. Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. Immunity. 2010;32:790–802.

    Article  CAS  PubMed  Google Scholar 

  107. Maritati M, Alessandro T, Zanotta N, Comar M, Bellini T, Sighinolfi L, et al. A comparison between different anti-retroviral therapy regimes on soluble inflammation markers: a pilot study. AIDS Res Ther. 2020;17:61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Babu H, Ambikan AT, Gabriel EE, Svensson Akusjarvi S, Palaniappan AN, Sundaraj V, et al. Systemic inflammation and the increased risk of inflamm-aging and age-associated diseases in people living with HIV on long term suppressive antiretroviral therapy. Front Immunol. 2019;10:1965.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Du Plessis N, Jacobs R, Gutschmidt A, Fang Z, van Helden PD, Lutz MB, et al. Phenotypically resembling myeloid derived suppressor cells are increased in children with HIV and exposed/infected with Mycobacterium tuberculosis. Eur J Immunol. 2017;47:107–18.

    Article  PubMed  Google Scholar 

  110. Marquez-Coello M, Montes de Oca Arjona M, Martin-Aspas A, Guerrero Sanchez F, Fernandez-Gutierrez Del Alamo C, Giron-Gonzalez JA. Antiretroviral therapy partially improves the abnormalities of dendritic cells and lymphoid and myeloid regulatory populations in recently infected HIV patients. Sci Rep. 2019;9:11654.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Grutzner EM, Hoffmann T, Wolf E, Gersbacher E, Neizert A, Stirner R, et al. Treatment intensification in HIV-infected patients is associated with reduced frequencies of regulatory T cells. Front Immunol. 2018;9:811.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Cai CW, Sereti I. Residual immune dysfunction under antiretroviral therapy. Semin Immunol. 2021;51:101471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chammartin F, Mocroft A, Egle A, Zangerle R, Smith C, Mussini C. Measures of longitudinal immune dysfunction and risk of AIDS and non-AIDS defining malignancies in antiretroviral treated people with human immunodeficiency virus (HIV). Clin Infect Dis. 2014;78:995–1004.

    Article  Google Scholar 

  114. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, et al. Relationship between T cell activation and CD4 + T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008;197:126–33.

    Article  PubMed  Google Scholar 

  115. Vassallo M, Mercie P, Cottalorda J, Ticchioni M, Dellamonica P. The role of lipopolysaccharide as a marker of immune activation in HIV-1 infected patients: a systematic literature review. Virol J. 2012;9:174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pandrea I, Cornell E, Wilson C, Ribeiro RM, Ma D, Kristoff J, et al. Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood. 2012;120:1357–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013;123:4595–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Flusberg DA, Sorger PK. Surviving apoptosis: life-death signaling in single cells. Trends Cell Biol. 2015;25:446–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, et al. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014;124:2626–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schaefer U, Voloshanenko O, Willen D, Walczak H. TRAIL: a multifunctional cytokine. Front Biosci. 2007;12:3813–24.

    Article  CAS  PubMed  Google Scholar 

  121. Rosado-Sanchez I, De Pablo-Bernal R, Rull A, Gonzalez J, Moreno S, Vinuesa D, et al. Increased frequencies of myeloid-derived suppressor cells precede immunodiscordance in HIV-infected subjects. Front Immunol. 2020;11:581307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. El-Mikkawy DME, El-Sadek MA, El-Badawy MA, Samaha D. Circulating level of interleukin-6 in relation to body mass indices and lipid profile in Egyptian adults with overweight and obesity. Egypt Rheumatol Rehabilit. 2020;47:7.

  123. Wei J, Xu H, Davies JL, Hemmings GP. Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci. 1992;51:1953–6.

    Article  CAS  PubMed  Google Scholar 

  124. Ferdin J, Goricar K, Dolzan V, Plemenitas A, Martin JN, Peterlin BM, et al. Viral protein Nef is detected in plasma of half of HIV-infected adults with undetectable plasma HIV RNA. PLoS One. 2018;13:e0191613.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Nefedova Y, Fishman M, Sherman S, Wang X, Beg AA, Gabrilovich DI. Mechanism of all-trans retinoic acid effect on tumor-associated myeloid-derived suppressor cells. Cancer Res. 2007;67:11021–8.

    Article  CAS  PubMed  Google Scholar 

  126. Draghiciu O, Nijman HW, Hoogeboom BN, Meijerhof T, Daemen T. Sunitinib depletes myeloid-derived suppressor cells and synergizes with a cancer vaccine to enhance antigen-specific immune responses and tumor eradication. Oncoimmunology 2015;4:e989764.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Varikuti S, Singh B, Volpedo G, Ahirwar DK, Jha BK, Saljoughian N, et al. Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells. Br J Cancer. 2020;122:1005–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Heine A, Schilling J, Grunwald B, Kruger A, Gevensleben H, Held SA, et al. The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib. Cancer Immunol Immunother. 2016;65:273–82.

    Article  CAS  PubMed  Google Scholar 

  129. Kao J, Ko EC, Eisenstein S, Sikora AG, Fu S, Chen SH. Targeting immune suppressing myeloid-derived suppressor cells in oncology. Crit Rev Oncol Hematol. 2011;77:12–9.

    Article  PubMed  Google Scholar 

  130. Forero A, Bendell JC, Kumar P, Janisch L, Rosen M, Wang Q, et al. First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Invest N Drugs. 2017;35:298–306.

    Article  CAS  Google Scholar 

  131. Leukes V, Walzl G, du Plessis N. Myeloid-derived suppressor cells as target of phosphodiesterase-5 inhibitors in host-directed therapeutics for tuberculosis. Front Immunol. 2020;11:451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Weed DT, Vella JL, Reis IM, De la Fuente AC, Gomez C, Sargi Z, et al. Tadalafil reduces myeloid-derived suppressor cells and regulatory T cells and promotes tumor immunity in patients with head and neck squamous cell carcinoma. Clin Cancer Res. 2015;21:39–48.

    Article  CAS  PubMed  Google Scholar 

  133. Reilley MJ, McCoon P, Cook C, Lyne P, Kurzrock R, Kim Y, et al. STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial. J Immunother Cancer. 2018;6:119.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Cui Y, Cai J, Wang W, Wang S. Regulatory effects of histone deacetylase inhibitors on myeloid-derived suppressor cells. Front Immunol. 2021;12:690207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Nishikawa G, Kawada K, Nakagawa J, Toda K, Ogawa R, Inamoto S, et al. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5. Cell Death Dis. 2019;10:264.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Qin H, Lerman B, Sakamaki I, Wei G, Cha SC, Rao SS, et al. Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nat Med. 2014;20:676–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wang Y, Zhang X, Yang L, Xue J, Hu G. Blockade of CCL2 enhances immunotherapeutic effect of anti-PD1 in lung cancer. J Bone Oncol. 2018;11:27–32.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Liu Z, Shi M, Ren Y, Xu H, Weng S, Ning W, et al. Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy. Mol Cancer. 2023;22:35.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Singh R, Chakraborty M, Gautam A, Roy SK, Halder I, Barber J, et al. Residual immune activation in HIV-Infected individuals expands monocytic-myeloid derived suppressor cells. Cell Immunol. 2021;362:104304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Mohammad Yaseen M, Mohammad Abuharfeil N, Darmani H. T-cell evasion and invasion during HIV-1 infection: the role of HIV-1 Tat protein. Cell Immunol. 2022;377:104554.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biotechnology and Genetic Engineering, Faculty of Science and Arts, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan

    Mahmoud Mohammad Yaseen, Nizar Mohammad Abuharfeil & Homa Darmani

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MMY contributed to writing all sections. NMA contributed to writing the introduction and conclusion. HD contributed to writing the introduction. MMY, NMA, and HD critically reviewed and validated the final version of this paper.

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Yaseen, M.M., Abuharfeil, N.M. & Darmani, H. MDSC expansion during HIV infection: regulators, ART and immune reconstitution. Genes Immun (2024). https://doi.org/10.1038/s41435-024-00272-9

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